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Sample records for biphasic synaptic ca

  1. Biphasic decay of the Ca transient results from increased sarcoplasmic reticulum Ca leak

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    Sankaranarayanan, Rajiv; Li, Yatong; Greensmith, David J.; Eisner, David A.

    2016-01-01

    Key points Ca leak from the sarcoplasmic reticulum through the ryanodine receptor (RyR) reduces the amplitude of the Ca transient and slows its rate of decay.In the presence of β‐adrenergic stimulation, RyR‐mediated Ca leak produces a biphasic decay of the Ca transient with a fast early phase and a slow late phase.Two forms of Ca leak have been studied, Ca‐sensitising (induced by caffeine) and non‐sensitising (induced by ryanodine) and both induce biphasic decay of the Ca transient.Only Ca‐sensitising leak can be reversed by traditional RyR inhibitors such as tetracaine.Ca leak can also induce Ca waves. At low levels of leak, waves occur. As leak is increased, first biphasic decay and then slowed monophasic decay is seen. The level of leak has major effects on the shape of the Ca transient. Abstract In heart failure, a reduction in Ca transient amplitude and contractile dysfunction can by caused by Ca leak through the sarcoplasmic reticulum (SR) Ca channel (ryanodine receptor, RyR) and/or decreased activity of the SR Ca ATPase (SERCA). We have characterised the effects of two forms of Ca leak (Ca‐sensitising and non‐sensitising) on calcium cycling and compared with those of SERCA inhibition. We measured [Ca2+]i with fluo‐3 in voltage‐clamped rat ventricular myocytes. Increasing SR leak with either caffeine (to sensitise the RyR to Ca activation) or ryanodine (non‐sensitising) had similar effects to SERCA inhibition: decreased systolic [Ca2+]i, increased diastolic [Ca2+]i and slowed decay. However, in the presence of isoproterenol, leak produced a biphasic decay of the Ca transient in the majority of cells while SERCA inhibition produced monophasic decay. Tetracaine reversed the effects of caffeine but not of ryanodine. When caffeine (1 mmol l−1) was added to a cell which displayed Ca waves, the wave frequency initially increased before waves disappeared and biphasic decay developed. Eventually (at higher caffeine concentrations), the

  2. Pycnogenol protects CA3-CA1 synaptic function in a rat model of traumatic brain injury.

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    Norris, Christopher M; Sompol, Pradoldej; Roberts, Kelly N; Ansari, Mubeen; Scheff, Stephen W

    2016-02-01

    Pycnogenol (PYC) is a patented mix of bioflavonoids with potent anti-oxidant and anti-inflammatory properties. Previously, we showed that PYC administration to rats within hours after a controlled cortical impact (CCI) injury significantly protects against the loss of several synaptic proteins in the hippocampus. Here, we investigated the effects of PYC on CA3-CA1 synaptic function following CCI. Adult Sprague-Dawley rats received an ipsilateral CCI injury followed 15 min later by intravenous injection of saline vehicle or PYC (10 mg/kg). Hippocampal slices from the injured (ipsilateral) and uninjured (contralateral) hemispheres were prepared at seven and fourteen days post-CCI for electrophysiological analyses of CA3-CA1 synaptic function and induction of long-term depression (LTD). Basal synaptic strength was impaired in slices from the ipsilateral, relative to the contralateral, hemisphere at seven days post-CCI and susceptibility to LTD was enhanced in the ipsilateral hemisphere at both post-injury timepoints. No interhemispheric differences in basal synaptic strength or LTD induction were observed in rats treated with PYC. The results show that PYC preserves synaptic function after CCI and provides further rationale for investigating the use of PYC as a therapeutic in humans suffering from neurotrauma. PMID:26607913

  3. The temporoammonic input to the hippocampal CA1 region displays distinctly different synaptic plasticity compared to the Schaffer collateral input in vivo: significance for synaptic information processing

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    Ayla eAksoy Aksel

    2013-08-01

    Full Text Available In terms of its sub-regional differentiation, the hippocampal CA1 region receives cortical information directly via the perforant (temporoammonic path (pp-CA1 synapse and indirectly via the tri-synaptic pathway where the last relay station is the Schaffer collateral-CA1 synapse (Sc-CA1 synapse. Research to date on pp-CA1 synapses has been conducted predominantly in vitro and never in awake animals, but these studies hint that information processing at this synapse might be distinct to processing at the Sc-CA1 synapse. Here, we characterized synaptic properties and synaptic plasticity at the pp-CA1 synapse of freely behaving adult rats. We established that field excitatory postsynaptic potentials at the pp-CA1 have longer onset latencies and a shorter time-to-peak compared to the Sc-CA1 synapse. LTP (> 24h was successfully evoked by tetanic afferent stimulation of pp-CA1 synapses. Low frequency stimulation evoked synaptic depression at Sc-CA1 synapses, but did not elicit LTD at pp-CA1 synapses unless the Schaffer collateral afferents to the CA1 region had been severed. Paired-pulse responses also showed significant differences. Our data suggest that synaptic plasticity at the pp-CA1 synapse is distinct from the Sc-CA1 synapse and that this may reflect its specific role in hippocampal information processing.

  4. Methamphetamine reduces LTP and increases baseline synaptic transmission in the CA1 region of mouse hippocampus.

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    Jarod Swant

    Full Text Available Methamphetamine (METH is an addictive psychostimulant whose societal impact is on the rise. Emerging evidence suggests that psychostimulants alter synaptic plasticity in the brain--which may partly account for their adverse effects. While it is known that METH increases the extracellular concentration of monoamines dopamine, serotonin, and norepinephrine, it is not clear how METH alters glutamatergic transmission. Within this context, the aim of the present study was to investigate the effects of acute and systemic METH on basal synaptic transmission and long-term potentiation (LTP; an activity-induced increase in synaptic efficacy in CA1 sub-field in the hippocampus. Both the acute ex vivo application of METH to hippocampal slices and systemic administration of METH decreased LTP. Interestingly, the acute ex vivo application of METH at a concentration of 30 or 60 microM increased baseline synaptic transmission as well as decreased LTP. Pretreatment with eticlopride (D2-like receptor antagonist did not alter the effects of METH on synaptic transmission or LTP. In contrast, pretreatment with D1/D5 dopamine receptor antagonist SCH23390 or 5-HT1A receptor antagonist NAN-190 abrogated the effect of METH on synaptic transmission. Furthermore, METH did not increase baseline synaptic transmission in D1 dopamine receptor haploinsufficient mice. Our findings suggest that METH affects excitatory synaptic transmission via activation of dopamine and serotonin receptor systems in the hippocampus. This modulation may contribute to synaptic maladaption induced by METH addiction and/or METH-mediated cognitive dysfunction.

  5. CaMKII Activity in the Ventral Tegmental Area Gates Cocaine-Induced Synaptic Plasticity in the Nucleus Accumbens

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    Liu, Xiaojie; Liu, Yong; Zhong, Peng; Wilkinson, Brianna; Qi, Jinshun; Olsen, Christopher M; Bayer, K. Ulrich; Liu, Qing-song

    2013-01-01

    Addictive drugs such as cocaine induce synaptic plasticity in discrete regions of the reward circuit. The aim of the present study is to investigate whether cocaine-evoked synaptic plasticity in the ventral tegmental area (VTA) and nucleus accumbens (NAc) is causally linked. Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a central regulator of long-term synaptic plasticity, learning, and drug addiction. We examined whether blocking CaMKII activity in the VTA affected cocaine conditio...

  6. Removal of Synaptic Ca2+-Permeable AMPA Receptors during Sleep.

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    Ulrich, Daniel; ROWAN, MICHAEL

    2011-01-01

    PUBLISHED here is accumulating evidence that sleep contributes to memory formation and learning, but the underlying cellular mechanisms are incompletely understood. To investigate the impact of sleep on excitatory synaptic transmission, we obtained whole-cell patch-clamp recordings from layer V pyramidal neurons in acute slices of somatosensory cortex of juvenile rats (postnatal days 21-25). In animals after the dark period, philanthotoxin 74 (PhTx)-sensitive calcium-permeable AMPA recepto...

  7. Synaptic mechanisms of pattern completion in the hippocampal CA3 network.

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    Guzman, Segundo Jose; Schlögl, Alois; Frotscher, Michael; Jonas, Peter

    2016-09-01

    The hippocampal CA3 region plays a key role in learning and memory. Recurrent CA3-CA3 synapses are thought to be the subcellular substrate of pattern completion. However, the synaptic mechanisms of this network computation remain enigmatic. To investigate these mechanisms, we combined functional connectivity analysis with network modeling. Simultaneous recording from up to eight CA3 pyramidal neurons revealed that connectivity was sparse, spatially uniform, and highly enriched in disynaptic motifs (reciprocal, convergence, divergence, and chain motifs). Unitary connections were composed of one or two synaptic contacts, suggesting efficient use of postsynaptic space. Real-size modeling indicated that CA3 networks with sparse connectivity, disynaptic motifs, and single-contact connections robustly generated pattern completion. Thus, macro- and microconnectivity contribute to efficient memory storage and retrieval in hippocampal networks. PMID:27609885

  8. Synaptic plasticity in the hippocampal area CA1-subiculum projection: implications for theories of memory.

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    O'Mara, S M; Commins, S; Anderson, M

    2000-01-01

    This paper reviews investigations of synaptic plasticity in the major, and underexplored, pathway from hippocampal area CA1 to the subiculum. This brain area is the major synaptic relay for the majority of hippocampal area CA1 neurons, making the subiculum the last relay of the hippocampal formation prior to the cortex. The subiculum thus has a very major role in mediating hippocampal-cortical interactions. We demonstrate that the projection from hippocampal area CA1 to the subiculum sustains plasticity on a number of levels. We show that this pathway is capable of undergoing both long-term potentiation (LTP) and paired-pulse facilitation (PPF, a short-term plastic effect). Although we failed to induce long-term depression (LTD) of this pathway with low-frequency stimulation (LFS) and two-pulse stimulation (TPS), both protocols can induce a "late-developing" potentiation of synaptic transmission. We further demonstrate that baseline synaptic transmission can be dissociated from paired-pulse stimulation of the same pathway; we also show that it is possible, using appropriate protocols, to change PPF to paired-pulse depression, thus revealing subtle and previously undescribed mechanisms which regulate short-term synaptic plasticity. Finally, we successfully recorded from individual subicular units in the freely-moving animal, and provide a description of the characteristics of such neurons in a pellet-chasing task. We discuss the implications of these findings in relation to theories of the biological consolidation of memory.

  9. Cholinergic-mediated IP3-receptor activation induces long-lasting synaptic enhancement in CA1 pyramidal neurons

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    Fernández de Sevilla, D.; Núñez Molina, Ángel; Borde, M.; Malinow, R.; Buño, Washinton

    2008-01-01

    Cholinergic-glutamatergic interactions influence forms of synaptic plasticity that are thought to mediate memory and learning. We tested in vitro the induction of long-lasting synaptic enhancement at Schaffer collaterals by acetylcholine (ACh) at the apical dendrite of CA1 pyramidal neurons and in vivo by stimulation of cholinergic afferents. In vitro ACh induced a Ca2+ wave and synaptic enhancement mediated by insertion of AMPA receptors in spines. Activation of muscarinic ACh receptors (mAC...

  10. Endocannabinoids differentially modulate synaptic plasticity in rat hippocampal CA1 pyramidal neurons.

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    Jian-Yi Xu

    Full Text Available BACKGROUND: Hippocampal CA1 pyramidal neurons receive two excitatory glutamatergic synaptic inputs: their most distal dendritic regions in the stratum lacunosum-moleculare (SLM are innervated by the perforant path (PP, originating from layer III of the entorhinal cortex, while their more proximal regions of the apical dendrites in the stratum radiatum (SR are innervated by the Schaffer-collaterals (SC, originating from hippocampal CA3 neurons. Endocannabinoids (eCBs are naturally occurring mediators capable of modulating both GABAergic and glutamatergic synaptic transmission and plasticity via the CB1 receptor. Previous work on eCB modulation of excitatory synapses in the CA1 region largely focuses on the SC pathway. However, little information is available on whether and how eCBs modulate glutamatergic synaptic transmission and plasticity at PP synapses. METHODOLOGY/PRINCIPAL FINDINGS: By employing somatic and dendritic patch-clamp recordings, Ca(2+ uncaging, and immunostaining, we demonstrate that there are significant differences in low-frequency stimulation (LFS- or DHPG-, an agonist of group I metabotropic glutamate receptors (mGluRs, induced long-term depression (LTD of excitatory synaptic transmission between SC and PP synapses in the same pyramidal neurons. These differences are eliminated by pharmacological inhibition with selective CB1 receptor antagonists or genetic deletion of the CB1 receptor, indicating that these differences likely result from differential modulation via a CB1 receptor-dependent mechanism. We also revealed that depolarization-induced suppression of excitation (DSE, a form of short-term synaptic plasticity, and photolysis of caged Ca(2+-induced suppression of Excitatory postsynaptic currents (EPSCs were less at the PP than that at the SC. In addition, application of WIN55212 (WIN induced a more pronounced inhibition of EPSCs at the SC when compared to that at the PP. CONCLUSIONS/SIGNIFICANCE: Our results suggest

  11. Dendritic spines as individual neuronal compartments for synaptic Ca2+ responses.

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    Müller, W; Connor, J A

    1991-11-01

    The possibility that postsynaptic spines on neuronal dendrites are discrete biochemical compartments for Ca(2+)-activated processes involved in synaptic plasticity is a widely proposed concept that has eluded experimental demonstration. Using microfluorometry on CA3 neurons in hippocampal slices, we show here that with weak presynaptic stimulation of associative/commissural fibres, Ca2+ accumulates in single postsynaptic spines but not in the parent dendrite. Stronger stimulation also promotes changes in dendrites. The NMDA-receptor antagonist AP-5 blocks changes in Ca2+ in spines. Sustained steep Ca2+ gradients between single spines and the parent dendrite, often lasting several minutes, develop with repeated stimulation. The observed compartmentalization allows for the specificity, cooperativity and associativity displayed by memory models such as long-term potentiation. PMID:1682815

  12. Regulation of Astroglia on Synaptic Plasticity in the CA1 Region of Rat Hippocampus

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    The regulation of astroglia on synaptic plasticity in the CA1 region of rat hippocampus was examined. Rats were divided into three groups: the newly born (<24 h), the juvenile (28-30days) and the adult groups (90-100 days), with each group having 20 animals. The CA1 region of rat hippocampus was immunohistochemically and electron-microscopically examined, respectively,for the growth of astroglia and the ultrastructure of synapses. The high performance liquid chromatography was employed to determine the cholesterol content of rat hippocampus. In the newly-born rats, a large number of neurons were noted in the hippocampal CA1 region of the newly-born rats,and few astroglia and no synaptic structure were observed. In the juvenile group, a few astroglias and some immature synapses were found, which were less than those in adult rats (P<0.01). The cholesterol content was 2.92±0.03 mg/g, 11.20± 3.41 mg/g and 12.91 ± 1.25 mg/g for newly born, the juvenile and the adult groups, respectively, with the differences among them being statistically significant (P<0.01). Our study suggests that the astrocytes may play an important role in the synaptic formation and functional maturity of hippocampal neurons, which may be related to the secretion of cholesterol from astrocytes.

  13. The cumulative analgesic effect of repeated electroacupuncture involves synaptic remodeling in the hippocampal CA3 region

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    Qiuling Xu; Tao Liu; Shuping Chen; Yonghui Gao; Junying Wang; Lina Qiao; Junling Liu

    2012-01-01

    In the present study, we examined the analgesic effect of repeated electroacupuncture at bilateral Zusanli (ST36) and Yanglingquan (GB34) once a day for 14 consecutive days in a rat model of chronic sciatic nerve constriction injury-induced neuropathic pain. In addition, concomitant changes in calcium/calmodulin-dependent protein kinase II expression and synaptic ultrastructure of neurons in the hippocampal CA3 region were examined. The thermal pain threshold (paw withdrawal latency) was increased significantly in both groups at 2 weeks after electroacupuncture intervention compared with 2 days of electroacupuncture. In ovariectomized rats with chronic constriction injury, the analgesic effect was significantly reduced. Electroacupuncture for 2 weeks significantly diminished the injury-induced increase in synaptic cleft width and thinning of the postsynaptic density, and it significantly suppressed the down-regulation of intracellular calcium/ calmodulin-dependent protein kinase II expression in the hippocampal CA3 region. Repeated electroacupuncture intervention had a cumulative analgesic effect on injury-induced neuropathic pain reactions, and it led to synaptic remodeling of hippocampal neurons and upregulated calcium/calmodulin-dependent protein kinase II expression in the hippocampal CA3 region.

  14. Novel nootropic dipeptide Noopept increases inhibitory synaptic transmission in CA1 pyramidal cells.

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    Kondratenko, Rodion V; Derevyagin, Vladimir I; Skrebitsky, Vladimir G

    2010-05-31

    Effects of newly synthesized nootropic and anxiolytic dipeptide Noopept on inhibitory synaptic transmission in hippocampal CA1 pyramidal cells were investigated using patch-clamp technique in whole-cell configuration. Bath application of Noopept (1 microM) significantly increased the frequency of spike-dependant spontaneous IPSCs whereas spike-independent mIPSCs remained unchanged. It was suggested that Noopept mediates its effect due to the activation of inhibitory interneurons terminating on CA1 pyramidal cells. Results of current clamp recording of inhibitory interneurons residing in stratum radiatum confirmed this suggestion. PMID:20382202

  15. Synaptic remodeling in the dentate gyrus, CA3, CA1, subiculum, and entorhinal cortex of mice: effects of deprived rearing and voluntary running.

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    Schaefers, Andrea T U; Grafen, Keren; Teuchert-Noodt, Gertraud; Winter, York

    2010-01-01

    Hippocampal cell proliferation is strongly increased and synaptic turnover decreased after rearing under social and physical deprivation in gerbils (Meriones unguiculatus). We examined if a similar epigenetic effect of rearing environment on adult neuroplastic responses can be found in mice (Mus musculus). We examined synaptic turnover rates in the dentate gyrus, CA3, CA1, subiculum, and entorhinal cortex. No direct effects of deprived rearing on rates of synaptic turnover were found in any of the studied regions. However, adult wheel running had the effect of leveling layer-specific differences in synaptic remodeling in the dentate gyrus, CA3, and CA1, but not in the entorhinal cortex and subiculum of animals of both rearing treatments. Epigenetic effects during juvenile development affected adult neural plasticity in mice, but seemed to be less pronounced than in gerbils. PMID:20508828

  16. Synaptic Remodeling in the Dentate Gyrus, CA3, CA1, Subiculum, and Entorhinal Cortex of Mice: Effects of Deprived Rearing and Voluntary Running

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    Andrea T. U. Schaefers

    2010-01-01

    Full Text Available Hippocampal cell proliferation is strongly increased and synaptic turnover decreased after rearing under social and physical deprivation in gerbils (Meriones unguiculatus. We examined if a similar epigenetic effect of rearing environment on adult neuroplastic responses can be found in mice (Mus musculus. We examined synaptic turnover rates in the dentate gyrus, CA3, CA1, subiculum, and entorhinal cortex. No direct effects of deprived rearing on rates of synaptic turnover were found in any of the studied regions. However, adult wheel running had the effect of leveling layer-specific differences in synaptic remodeling in the dentate gyrus, CA3, and CA1, but not in the entorhinal cortex and subiculum of animals of both rearing treatments. Epigenetic effects during juvenile development affected adult neural plasticity in mice, but seemed to be less pronounced than in gerbils.

  17. Correlation between synaptic protein expression and synaptic reorganization in the hippocampal CA3 region in a rat model of post-traumatic epilepsy

    Institute of Scientific and Technical Information of China (English)

    Gaolian Zhang; Jianmin Huang; Bang Zhao; Haineng Huang; Yuanyang Deng; Huadong Huang; Qirong He; Jianping Liang

    2010-01-01

    Postsynaptic density protein-95 and synaptophysin participate in synaptic reorganization in the forebrain of epilepsy models.However,the time-effect relationship between dynamic synapsin expression in hippocampus and synaptic reorganization in the post-traumatic epilepsy model remains unclear.FeCl2 was injected into the hippocampal CA3 region of the right forebrain in rats to induce post-traumatic epilepsy.Postsynaptic density protein-95 and synaptophysin expression was detected using immunohistochemistry.Epileptiform discharge induced by FeCl2 injection was determined in rat forebrain neurons,revealing decreased postsynaptic density protein-95expression at 24 hours and lowest levels at 7 days.Synaptophysin expression was markedly reduced at 24 hours,but increased at 7 days.Postsynaptic density protein-95 and synaptophysin expression was consistent with abnormal mossy fiber sprouting and synaptic reorganization following neuronal injury in the hippocampal CA3 region of FeCl2-induced epilepsy models.

  18. Dynamics of free intracellular Ca2+ during synaptic and spike activity of cricket tibial motoneurons.

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    Baden, Tom; Hedwig, Berthold

    2009-04-01

    For all nervous systems, motoneurons are the main output pathway. They are involved in generating episodic motor activity as well as enduring motor rhythms. To determine whether changes in cytosolic Ca(2+) correlate with motor performance, we studied the spatiotemporal dynamics, mode of entry and role of free intracellular Ca(2+) in cricket (Gryllus bimaculatus) front leg tibial extensor and flexor motoneurons. Synaptic activation or intracellular depolarising current injection uniformly increased Ca(2+) with the same dynamics throughout the primary and secondary branches of the dendritic tree of all motoneurons. Ca(2+) rise times (mean tau(rise), 233-295 ms) were lower than decay times (mean tau(decay), 1927-1965 ms), and resulted in a Ca(2+) plateau during repetitive activation, such as during walking. The neurons therefore operate with a different Ca(2+) level during walking than during episodic leg movements. Ca(2+) enters the dendritic processes of motoneurons via a voltage-activated mechanism. Entry is driven by subthreshold excitation, and is largely independent of the neurons' spiking activity. To what extent ligand-activated mechanisms of Ca(2+) entry operate remains uncertain. We found no evidence for any prominent Ca(2+)-activated secondary currents in these motoneurons. Excitatory postsynaptic potentials evoked by extracellular stimulation of descending neurons were unaffected by the level of free intracellular Ca(2+). The activity of tibial motoneurons therefore appears to be only weakly dependent on the level of free intracellular Ca(2+) in dendrites. This is different to what has been found for many other neurons studied, and may represent an essential prerequisite for insect motoneurons to support a wide range of both episodic and rhythmic motor sequences underlying behaviour.

  19. M-type potassium channels modulate Schaffer collateral-CA1 glutamatergic synaptic transmission.

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    Sun, Jianli; Kapur, Jaideep

    2012-08-15

    Previous studies have suggested that muscarinic receptor activation modulates glutamatergic transmission. M-type potassium channels mediate the effects of muscarinic activation in the hippocampus, and it has been proposed that they modulate glutamatergic synaptic transmission. We tested whether M1 muscarinic receptor activation enhances glutamatergic synaptic transmission via the inhibition of the M-type potassium channels that are present in Schaffer collateral axons and terminals. Miniature excitatory postsynaptic currents (mEPSCs) were recorded from CA1 pyramidal neurons. The M1 receptor agonist, NcN-A-343, increased the frequency of mEPSCs, but did not alter their amplitude. The M-channel blocker XE991 and its analogue linopirdine also increased the frequency of mEPSCs. Flupirtine, which opens M-channels, had the opposite effect. XE991 did not enhance mEPSCs frequency in a calcium-free external medium. Blocking P/Q- and N-type calcium channels abolished the effect of XE991 on mEPSCs. These data suggested that the inhibition of M-channels increases presynaptic calcium-dependent glutamate release in CA1 pyramidal neurons. The effects of these agents on the membrane potentials of presynaptic CA3 pyramidal neurons were studied using current clamp recordings; activation of M1 receptors and blocking M-channels depolarized neurons and increased burst firing. The input resistance of CA3 neurons was increased by the application of McN-A-343 and XE991; these effects were consistent with the closure of M-channels. Muscarinic activation inhibits M-channels in CA3 pyramidal neurons and its efferents – Schaffer collateral, which causes the depolarization, activates voltage-gated calcium channels, and ultimately elevates the intracellular calcium concentration to increase the release of glutamate on CA1 pyramidal neurons. PMID:22674722

  20. Melamine Alters Glutamatergic Synaptic Transmission of CA3-CA1 Synapses Presynaptically Through Autophagy Activation in the Rat Hippocampus.

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    Zhang, Hui; Wang, Hui; Xiao, Xi; Zhang, Tao

    2016-01-01

    Melamine is an industrial chemical that can cause central nervous system disorders including excitotoxicity and cognitive impairment. Its illegal use in powdered baby formula was the focus of a milk scandal in China in 2008. One of our previous studies showed that melamine impaired glutamatergic transmission in rat hippocampal CA1 pyramidal cells. However, the underlying mechanism of action of melamine is unclear, and it is unknown if the CA3-CA1 pathway is directly involved. In the present study, a whole-cell patch-clamp technique was employed to investigate the effect of melamine on the hippocampal CA3-CA1 pathway in vitro. Both the evoked excitatory postsynaptic current (eEPSC) and the paired-pulse ratio (PPR) were recorded. Furthermore, we examined whether autophagy was involved in glutamatergic transmission alterations induced by melamine. Our data showed that melamine significantly increased the amplitude of eEPSCs in a dose-dependent manner. Inhibition of the N-methyl-D-aspartic acid receptor did not prevent the increase in eEPSC amplitude. In addition, the PPR was remarkably decreased by a melamine concentration of 5 × 10(-5) g/mL. It was found that autophagy could be activated by melamine and an autophagy inhibitor, 3-MA, prevented the melamine-induced increase in eEPSC amplitude. Overall, our results show that melamine presynaptically alters glutamatergic synaptic transmission of hippocampal CA3-CA1 synapses in vitro and this is likely associated with autophagy alteration. PMID:26530910

  1. Graphene Oxide Nanosheets Disrupt Lipid Composition, Ca(2+) Homeostasis, and Synaptic Transmission in Primary Cortical Neurons.

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    Bramini, Mattia; Sacchetti, Silvio; Armirotti, Andrea; Rocchi, Anna; Vázquez, Ester; León Castellanos, Verónica; Bandiera, Tiziano; Cesca, Fabrizia; Benfenati, Fabio

    2016-07-26

    Graphene has the potential to make a very significant impact on society, with important applications in the biomedical field. The possibility to engineer graphene-based medical devices at the neuronal interface is of particular interest, making it imperative to determine the biocompatibility of graphene materials with neuronal cells. Here we conducted a comprehensive analysis of the effects of chronic and acute exposure of rat primary cortical neurons to few-layer pristine graphene (GR) and monolayer graphene oxide (GO) flakes. By combining a range of cell biology, microscopy, electrophysiology, and "omics" approaches we characterized the graphene-neuron interaction from the first steps of membrane contact and internalization to the long-term effects on cell viability, synaptic transmission, and cell metabolism. GR/GO flakes are found in contact with the neuronal membrane, free in the cytoplasm, and internalized through the endolysosomal pathway, with no significant impact on neuron viability. However, GO exposure selectively caused the inhibition of excitatory transmission, paralleled by a reduction in the number of excitatory synaptic contacts, and a concomitant enhancement of the inhibitory activity. This was accompanied by induction of autophagy, altered Ca(2+) dynamics, and a downregulation of some of the main players in the regulation of Ca(2+) homeostasis in both excitatory and inhibitory neurons. Our results show that, although graphene exposure does not impact neuron viability, it does nevertheless have important effects on neuronal transmission and network functionality, thus warranting caution when planning to employ this material for neurobiological applications. PMID:27359048

  2. Molecular evidence of synaptic pathology in the CA1 region in schizophrenia

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    Matosin, Natalie; Fernandez-Enright, Francesca; Lum, Jeremy S; Engel, Martin; Andrews, Jessica L; Gassen, Nils C; Wagner, Klaus V; Schmidt, Mathias V; Newell, Kelly A

    2016-01-01

    Alterations of postsynaptic density (PSD)95-complex proteins in schizophrenia ostensibly induce deficits in synaptic plasticity, the molecular process underlying cognitive functions. Although some PSD95-complex proteins have been previously examined in the hippocampus in schizophrenia, the status of other equally important molecules is unclear. This is especially true in the cornu ammonis (CA)1 hippocampal subfield, a region that is critically involved in the pathophysiology of the illness. We thus performed a quantitative immunoblot experiment to examine PSD95 and several of its associated proteins in the CA1 region, using post mortem brain samples derived from schizophrenia subjects with age-, sex-, and post mortem interval-matched controls (n=20/group). Our results indicate a substantial reduction in PSD95 protein expression (−61.8%). Further analysis showed additional alterations to the scaffold protein Homer1 (Homer1a: +42.9%, Homer1b/c: −24.6%), with a twofold reduction in the ratio of Homer1b/c:Homer1a isoforms (P=0.011). Metabotropic glutamate receptor 1 (mGluR1) protein levels were significantly reduced (−32.7%), and Preso, a protein that supports interactions between Homer1 or PSD95 with mGluR1, was elevated (+83.3%). Significant reduction in synaptophysin (−27.8%) was also detected, which is a validated marker of synaptic density. These findings support the presence of extensive molecular abnormalities to PSD95 and several of its associated proteins in the CA1 region in schizophrenia, offering a small but significant step toward understanding how proteins in the PSD are altered in the schizophrenia brain, and their relevance to overall hippocampal and cognitive dysfunction in the illness. PMID:27430010

  3. SCRAPPER regulates the thresholds of long-term potentiation/depression, the bidirectional synaptic plasticity in hippocampal CA3-CA1 synapses.

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    Takagi, Hiroshi; Setou, Mitsutoshi; Ito, Seiji; Yao, Ikuko

    2012-01-01

    SCRAPPER, which is an F-box protein encoded by FBXL20, regulates the frequency of the miniature excitatory synaptic current through the ubiquitination of Rab3-interacting molecule 1. Here, we recorded the induction of long-term potentiation/depression (LTP/LTD) in CA3-CA1 synapses in E3 ubiquitin ligase SCRAPPER-deficient hippocampal slices. Compared to wild-type mice, Scrapper-knockout mice exhibited LTDs with smaller magnitudes after induction with low-frequency stimulation and LTPs with larger magnitudes after induction with tetanus stimulation. These findings suggest that SCRAPPER regulates the threshold of bidirectional synaptic plasticity and, therefore, metaplasticity. PMID:23316391

  4. SCRAPPER Regulates the Thresholds of Long-Term Potentiation/Depression, the Bidirectional Synaptic Plasticity in Hippocampal CA3-CA1 Synapses

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    Hiroshi Takagi

    2012-01-01

    Full Text Available SCRAPPER, which is an F-box protein encoded by FBXL20, regulates the frequency of the miniature excitatory synaptic current through the ubiquitination of Rab3-interacting molecule 1. Here, we recorded the induction of long-term potentiation/depression (LTP/LTD in CA3-CA1 synapses in E3 ubiquitin ligase SCRAPPER-deficient hippocampal slices. Compared to wild-type mice, Scrapper-knockout mice exhibited LTDs with smaller magnitudes after induction with low-frequency stimulation and LTPs with larger magnitudes after induction with tetanus stimulation. These findings suggest that SCRAPPER regulates the threshold of bidirectional synaptic plasticity and, therefore, metaplasticity.

  5. Midbrain dopamine neurons bidirectionally regulate CA3-CA1 synaptic drive.

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    Rosen, Zev B; Cheung, Stephanie; Siegelbaum, Steven A

    2015-12-01

    Dopamine (DA) is required for hippocampal-dependent memory and long-term potentiation (LTP) at CA1 Schaffer collateral (SC) synapses. It is therefore surprising that exogenously applied DA has little effect on SC synapses, but suppresses CA1 perforant path (PP) inputs. To examine DA actions under more physiological conditions, we used optogenetics to release DA from ventral tegmental area inputs to hippocampus. Unlike exogenous DA application, optogenetic release of DA caused a bidirectional, activity-dependent modulation of SC synapses, with no effect on PP inputs. Low levels of DA release, simulating tonic DA neuron firing, depressed the SC response through a D4 receptor-dependent enhancement of feedforward inhibition mediated by parvalbumin-expressing interneurons. Higher levels of DA release, simulating phasic firing, increased SC responses through a D1 receptor-dependent enhancement of excitatory transmission. Thus, tonic-phasic transitions in DA neuron firing in response to motivational demands may cause a modulatory switch from inhibition to enhancement of hippocampal information flow.

  6. Extracellular cGMP Modulates Learning Biphasically by Modulating Glycine Receptors, CaMKII and Glutamate-Nitric Oxide-cGMP Pathway

    Science.gov (United States)

    Cabrera-Pastor, Andrea; Malaguarnera, Michele; Taoro-Gonzalez, Lucas; Llansola, Marta; Felipo, Vicente

    2016-01-01

    It has been proposed that extracellular cGMP modulates the ability to learn a Y maze task, but the underlying mechanisms remained unknown. Here we show that extracellular cGMP, at physiological concentrations, modulates learning in the Y maze in a biphasic way by modulating the glutamate-nitric oxide-cGMP pathway in cerebellum. Extracellular cGMP reduces glycine receptors activation inducing a voltage-dependent calcium-channels-mediated increase of calcium in Purkinje neurons. This calcium increase modulates CaMKII phosphorylation in a biphasic way. When basal calcium concentration is low extracellular cGMP reduces CaMKII phosphorylation, increasing nitric oxide synthase activity, the glutamate-NO-cGMP pathway function and learning ability. When basal calcium is normal extracellular cGMP increases CaMKII phosphorylation, reducing nitric oxide synthase activity, the pathway function and learning. These data unveil new mechanisms modulating learning in the Y maze and likely other learning types which may be therapeutic targets to improve learning in pathological situations associated with altered cGMP levels. PMID:27634333

  7. Extracellular cGMP Modulates Learning Biphasically by Modulating Glycine Receptors, CaMKII and Glutamate-Nitric Oxide-cGMP Pathway.

    Science.gov (United States)

    Cabrera-Pastor, Andrea; Malaguarnera, Michele; Taoro-Gonzalez, Lucas; Llansola, Marta; Felipo, Vicente

    2016-01-01

    It has been proposed that extracellular cGMP modulates the ability to learn a Y maze task, but the underlying mechanisms remained unknown. Here we show that extracellular cGMP, at physiological concentrations, modulates learning in the Y maze in a biphasic way by modulating the glutamate-nitric oxide-cGMP pathway in cerebellum. Extracellular cGMP reduces glycine receptors activation inducing a voltage-dependent calcium-channels-mediated increase of calcium in Purkinje neurons. This calcium increase modulates CaMKII phosphorylation in a biphasic way. When basal calcium concentration is low extracellular cGMP reduces CaMKII phosphorylation, increasing nitric oxide synthase activity, the glutamate-NO-cGMP pathway function and learning ability. When basal calcium is normal extracellular cGMP increases CaMKII phosphorylation, reducing nitric oxide synthase activity, the pathway function and learning. These data unveil new mechanisms modulating learning in the Y maze and likely other learning types which may be therapeutic targets to improve learning in pathological situations associated with altered cGMP levels. PMID:27634333

  8. Astragaloside Ⅳ inhibits spontaneous synaptic transmission and synchronized Ca2+ oscillations on hippocampal neurons

    Institute of Scientific and Technical Information of China (English)

    Shao-qing ZHU; Lei QI; Yan-fang RUI; Ru-xin LI; Xiang-ping HE; Zuo-ping XIE

    2008-01-01

    Aim: To investigate the changes in the spontaneous neuronal excitability in-duced by astragaloside Ⅳ (AGS-Ⅳ) in the cultured hippocampal network. Methods: Hippocampal neurons in culture for 9-11 d were used for this study. The sponta-neous synaptic activities of these hippocampal neurons were examined by Ca2+ imaging and whole-cell patch-clamp techniques. In total, 40 mg/L AGS-Ⅳ dis-solved in DMSO and 2 mL/L DMSO were applied to the neurons under a micro-scope while the experiments were taking place. Results: AGS-Ⅳ inhibited the frequencies of synchronized spontaneous Ca2+ oscillations to 59.39%+3.25% (mean+SEM), the spontaneous postsynaptic currents to 43.78%±7.72% (mean±SEM), and the spontaneous excitatory postsynaptic currents to 49.25%±7.06% (mean±SEM) of those of the control periods, respectively, at 16 min after the AGS-Ⅳ applications. AGS-Ⅳ also decreased the peak values of the voltage-gated K+ and Na+ channel currents at that time point. Conclusion: These results indicate that AGS-Ⅳ suppresses the spontaneous neuronal excitabilities effectively. Such a modulation of neuronal activity could represent new evidence for AGS-Ⅳ as a neuroprotector.

  9. CAPS1 stabilizes the state of readily releasable synaptic vesicles to fusion competence at CA3–CA1 synapses in adult hippocampus

    Science.gov (United States)

    Shinoda, Yo; Ishii, Chiaki; Fukazawa, Yugo; Sadakata, Tetsushi; Ishii, Yuki; Sano, Yoshitake; Iwasato, Takuji; Itohara, Shigeyoshi; Furuichi, Teiichi

    2016-01-01

    Calcium-dependent activator protein for secretion 1 (CAPS1) regulates exocytosis of dense-core vesicles in neuroendocrine cells and of synaptic vesicles in neurons. However, the synaptic function of CAPS1 in the mature brain is unclear because Caps1 knockout (KO) results in neonatal death. Here, using forebrain-specific Caps1 conditional KO (cKO) mice, we demonstrate, for the first time, a critical role of CAPS1 in adult synapses. The amplitude of synaptic transmission at CA3–CA1 synapses was strongly reduced, and paired-pulse facilitation was significantly increased, in acute hippocampal slices from cKO mice compared with control mice, suggesting a perturbation in presynaptic function. Morphological analysis revealed an accumulation of synaptic vesicles in the presynapse without any overall morphological change. Interestingly, however, the percentage of docked vesicles was markedly decreased in the Caps1 cKO. Taken together, our findings suggest that CAPS1 stabilizes the state of readily releasable synaptic vesicles, thereby enhancing neurotransmitter release at hippocampal synapses. PMID:27545744

  10. Differential alterations of synaptic plasticity in dentate gyrus and CA1 hippocampal area of Calbindin-D28K knockout mice

    NARCIS (Netherlands)

    Westerink, R.H.S.; Beekwilder, J.P.; Wadman, W.J.

    2012-01-01

    Regulation of the intracellular calcium concentration ([Ca(2+)](i)) is of critical importance for synaptic function. Therefore, neurons buffer [Ca(2+)](i) using intracellular Ca(2+)-binding proteins (CaBPs). Previous evidence suggests that Calbindin-D(28K) (CB), an abundantly expressed endogenous fa

  11. Activated CaMKII Couples GluN2B and Casein Kinase 2 to Control Synaptic NMDA Receptors

    Directory of Open Access Journals (Sweden)

    Antonio Sanz-Clemente

    2013-03-01

    Full Text Available Synaptic activity triggers a profound reorganization of the molecular composition of excitatory synapses. For example, NMDA receptors are removed from synapses in an activity- and calcium-dependent manner, via casein kinase 2 (CK2 phosphorylation of the PDZ ligand of the GluN2B subunit (S1480. However, how synaptic activity drives this process remains unclear because CK2 is a constitutively active kinase, which is not directly regulated by calcium. We show here that activated CaMKII couples GluN2B and CK2 to form a trimolecular complex and increases CK2-mediated phosphorylation of GluN2B S1480. In addition, a GluN2B mutant, which contains an insert to mimic the GluN2A sequence and cannot bind to CaMKII, displays reduced S1480 phosphorylation and increased surface expression. We find that although disrupting GluN2B/CaMKII binding reduces synapse number, it increases synaptic-GluN2B content. Therefore, the GluN2B/CaMKII association controls synapse density and PSD composition in an activity-dependent manner, including recruitment of CK2 for the removal of GluN2B from synapses.

  12. Boosting of synaptic potentials and spine Ca transients by the peptide toxin SNX-482 requires alpha-1E-encoded voltage-gated Ca channels.

    Directory of Open Access Journals (Sweden)

    Andrew J Giessel

    Full Text Available The majority of glutamatergic synapses formed onto principal neurons of the mammalian central nervous system are associated with dendritic spines. Spines are tiny protuberances that house the proteins that mediate the response of the postsynaptic cell to the presynaptic release of glutamate. Postsynaptic signals are regulated by an ion channel signaling cascade that is active in individual dendritic spines and involves voltage-gated calcium (Ca channels, small conductance (SK-type Ca-activated potassium channels, and NMDA-type glutamate receptors. Pharmacological studies using the toxin SNX-482 indicated that the voltage-gated Ca channels that signal within spines to open SK channels belong to the class Ca(V2.3, which is encoded by the Alpha-1E pore-forming subunit. In order to specifically test this conclusion, we examined the effects of SNX-482 on synaptic signals in acute hippocampal slices from knock-out mice lacking the Alpha-1E gene. We find that in these mice, application of SNX-482 has no effect on glutamate-uncaging evoked synaptic potentials and Ca influx, indicating that that SNX-482 indeed acts via the Alpha-1E-encoded Ca(V2.3 channel.

  13. Synaptic Vesicle Tethering and the CaV2.2 Distal C-terminal

    Directory of Open Access Journals (Sweden)

    Fiona K Wong

    2014-03-01

    Full Text Available . Evidence that synaptic vesicles (SVs can be gated by a single voltage sensitive calcium channel (CaV2.2 predict a molecular linking mechanism or ‘tether’[Stanley 1993]. Recent studies have proposed that the SV binds to the distal C-terminal on the CaV2.2 calcium channel [Kaeser et al. 2011;Wong, Li, and Stanley 2013] while genetic analysis proposed a double tether mechanism via RIM: directly to the C terminus PDZ ligand domain or indirectly via a more proximal proline rich site [Kaeser et al. 2011]. Using a novel in vitro SV-PD binding assay, we reported that SVs bind to a fusion protein comprising the C-terminal distal third (C3, aa 2137-2357 [Wong, Li, and Stanley 2013]. Here we limit the binding site further to the last 58 aa, beyond the proline rich site, by the absence of SV capture by a truncated C3 fusion protein (aa 2137-2299. To test PDZ-dependent binding we generated two C terminus-mutant C3 fusion proteins and a mimetic blocking peptide (H-WC, aa 2349-2357 and validated these by elimination of MINT-1 or RIM binding. Persistence of SV capture with all three fusion proteins or with the full length C3 protein but in the presence of the blocking peptide, demonstrated that SVs can bind to the distal C-terminal via a PDZ-independent mechanism. These results were supported in situ by normal SV turnover in H-WC-loaded synaptosomes, as assayed by a novel peptide cryoloading method. Thus, SVs tether to the CaV2.2 C-terminal within a 49 aa region immediately prior to the terminus PDZ ligand domain. Long tethers that could reflect extended C termini were imaged by electron microscopy of synaptosome ghosts. To fully account for SV tethering we propose a model where SVs are initially captured, or ‘grabbed’, from the cytoplasm by a binding site on the distal region of the channel C-terminal and are then retracted to be ‘locked’ close to the channel by a second attachment mechanism in preparation for single channel domain gating.

  14. Estrogen and Aging Affect Synaptic Distribution of Phosphorylated LIM Kinase (LIMK) in CA1 Region of Female Rat Hippocampus

    OpenAIRE

    Yildirim, Murat; JANSSEN, WILLIAM G.M.; Tabori, Nora E.; Adams, Michelle M.; Yuen, Genevieve S.; Akama, Keith T.; McEwen, Bruce S.; Milner, Teresa A.; Morrison, John H.

    2008-01-01

    17β-Estradiol (E) increases axospinous synapse density in the hippocampal CA1 region of young female rats, but not in aged rats. This may be linked to age-related alterations in signaling pathways activated by synaptic estrogen receptor α (ER-α) that potentially regulate spine formation, such as LIM-Kinase (LIMK), an actin depolymerizing factor/cofilin kinase. We hypothesized that, as with ER-α, phospho-LIMK (pLIMK) may be less abundant or responsive to E in CA1 synapses of aged female rats. ...

  15. SCRAPPER Regulates the Thresholds of Long-Term Potentiation/Depression, the Bidirectional Synaptic Plasticity in Hippocampal CA3-CA1 Synapses

    OpenAIRE

    Hiroshi Takagi; Mitsutoshi Setou; Seiji Ito; Ikuko Yao

    2012-01-01

    SCRAPPER, which is an F-box protein encoded by FBXL20, regulates the frequency of the miniature excitatory synaptic current through the ubiquitination of Rab3-interacting molecule 1. Here, we recorded the induction of long-term potentiation/depression (LTP/LTD) in CA3-CA1 synapses in E3 ubiquitin ligase SCRAPPER-deficient hippocampal slices. Compared to wild-type mice, Scrapper-knockout mice exhibited LTDs with smaller magnitudes after induction with low-frequency stimulation and LTPs with la...

  16. Voluntary running depreciates the requirement of Ca2+-stimulated cAMP signaling in synaptic potentiation and memory formation.

    Science.gov (United States)

    Zheng, Fei; Zhang, Ming; Ding, Qi; Sethna, Ferzin; Yan, Lily; Moon, Changjong; Yang, Miyoung; Wang, Hongbing

    2016-08-01

    Mental health and cognitive functions are influenced by both genetic and environmental factors. Although having active lifestyle with physical exercise improves learning and memory, how it interacts with the specific key molecular regulators of synaptic plasticity is largely unknown. Here, we examined the effects of voluntary running on long-term potentiation (LTP) and memory formation in mice lacking type 1 adenylyl cyclase (AC1), a neurospecific synaptic enzyme that contributes to Ca(2+)-stimulated cAMP production. Following 1 mo of voluntary running-wheel exercise, the impaired LTP and object recognition memory in AC1 knockout (KO) mice were significantly attenuated. Running up-regulated exon II mRNA level of BDNF (brain-derived neurotrophic factor), though it failed to increase exon I and IV mRNAs in the hippocampus of AC1 KO mice. Intrahippocampal infusion of recombinant BDNF was sufficient to rescue LTP and object recognition memory defects in AC1 KO mice. Therefore, voluntary running and exogenous BDNF application overcome the defective Ca(2+)-stimulated cAMP signaling. Our results also demonstrate that alteration in Ca(2+)-stimulated cAMP can affect the molecular outcome of physical exercise. PMID:27421897

  17. EFFECTS OF ESTROGEN AND AGING ON THE SYNAPTIC DISTRIBUTION OF PHOSPHORYLATED AKT-IMMUNOREACTIVITY IN THE CA1 REGION OF THE FEMALE RAT HIPPOCAMPUS

    OpenAIRE

    Yildirim, Murat; JANSSEN, WILLIAM G.M.; Lou, W.Y. Wendy; Akama, Keith T.; McEwen, Bruce S.; Milner, Teresa A.; Morrison, John H.

    2010-01-01

    The estrogen 17β-estradiol (E) increases the axospinous synaptic density and plasticity in the hippocampal CA1 region of young female rats but fails to do so in aged female rats. This E stimulus on synaptic plasticity is associated with the phosphorylation-dependent activation of Akt kinase. Our previous findings demonstrated that increased estrogen levels subsequently increase phosphorylated Akt (pAkt)-immunoreactivity (-IR) within the dendritic shafts and spines of pyramidal neurons in youn...

  18. The functional nature of synaptic circuitry is altered in area CA3 of the hippocampus in a mouse model of Down's syndrome

    Science.gov (United States)

    Hanson, Jesse E; Blank, Martina; Valenzuela, Ricardo A; Garner, Craig C; Madison, Daniel V

    2007-01-01

    Down's syndrome (DS) is the most common cause of mental retardation, and memory impairments are more severe in DS than in most if not all other causes of mental retardation. The Ts65Dn mouse, a genetic model of DS, exhibits phenotypes of DS, including memory impairments indicative of hippocampal dysfunction. We examined functional synaptic connectivity in area CA3 of the hippocampus of Ts65Dn mice using organotypic slice cultures as a model. We found reductions in multiple measures of synaptic function in both excitatory and inhibitory inputs to pyramidal neurons in CA3 of the Ts65Dn hippocampus. However, associational synaptic connections between pyramidal neurons were more abundant and more likely to be active rather than silent in the Ts65Dn hippocampus. Synaptic potentiation was normal in these associational connections. Decreased overall functional synaptic input onto pyramidal neurons expressed along with the specific hyperconnectivity of associational connections between pyramidal neurons will result in predictable alterations of CA3 network function, which may contribute to the memory impairments seen in DS. PMID:17158177

  19. Genistein Inhibits Aβ25-35-Induced Synaptic Toxicity and Regulates CaMKII/CREB Pathway in SH-SY5Y Cells.

    Science.gov (United States)

    Xi, Yuan-Di; Zhang, Dan-Di; Ding, Juan; Yu, Huan-Ling; Yuan, Lin-Hong; Ma, Wei-Wei; Han, Jing; Xiao, Rong

    2016-10-01

    Genistein (Gen), as a functional food in human diet, has shown many beneficial effects on neurodegenerative diseases such as Alzheimer's disease (AD). But the neuroprotective mechanism of Gen is not clear. Because synaptic failure is considered as the earliest phase in the pathogenesis of AD, we try to validate our hypothesis that synapse may be one target of Gen on protecting neurons. In this study, SH-SY5Y cells were pre-incubated with or without Gen for 2 h followed by the incubation with Aβ25-35 (25 μmol/L) for another 24 h. Flow cytometry, Western Blots, and RT-PCR analysis were used to test the synaptic factors. The data showed that Gen pre-treatment could reverse the Aβ25-35-induced down-regulation of synaptophysin and postsynaptic marker postsynaptic density-95. In addition, the down-regulation of NR1 and NR2B induced by Aβ25-35 which are subunits of N-methyl-D-aspartate receptor also could be antagonized by pre-treatment of Gen. Moreover, the factors of CaMKII/CREB signaling pathway were detected. The results showed that mRNA and protein expressions of (Ca(2+))/calmodulin(CaM), CaMKII/pCaMKII, and CREB/pCREB were significantly down-regulated by Aβ25-35, but they were all restored by the pre-treatment of Gen. Furthermore, Gen also maintained the intracellular Ca(2+) concentration which was disturbed by Aβ25-35. In conclusion, these results suggested that Gen could protect synaptic dysfunction induced by Aβ, and the mechanism might be associated with the regulation of synaptic markers and Ca(2+) level through activating CaM/CaMK/CREB signaling pathway. PMID:26658733

  20. Complexin inhibits spontaneous release and synchronizes Ca2+-triggered synaptic vesicle fusion by distinct mechanisms

    OpenAIRE

    Lai, Ying; Diao, Jiajie; Cipriano, Daniel J.; Zhang, Yunxiang; Pfuetzner, Richard A.; Padolina, Mark S; Brunger, Axel T.

    2014-01-01

    Previously we showed that fast Ca2+-triggered vesicle fusion with reconstituted neuronal SNAREs and synaptotagmin-1 begins from an initial hemifusion-free membrane point contact, rather than a hemifusion diaphragm, using a single vesicle–vesicle lipid/content mixing assay (Diao et al., 2012). When complexin-1 was included, a more pronounced Ca2+-triggered fusion burst was observed, effectively synchronizing the process. Here we show that complexin-1 also reduces spontaneous fusion in the same...

  1. Deoxyschisandrin modulates synchronized Ca2+ oscillations and spontaneous synaptic transmission of cultured hippocampal neurons

    Institute of Scientific and Technical Information of China (English)

    Min FU; Zhao-hui SUN; Min ZONG; Xiang-ping HE; Huan-cong ZUO; Zuo-ping XIE

    2008-01-01

    Aim: Deoxyschisandrin is one of the most effective composites of Schisandra chinensis, a famous Chinese medicine widely used as an antistress, anti-aging, and neurological performance-improving herb. In this study, we examined its spe- cific mechanisms of action on cultured hippocampal neurons. Methods: Hippoc- ampal neurons, primarily cultured for 9-11 d in vitro, were used for this study. DS were dissolved in DMSO and applied to calcium imaging and whole-cell patch clamp. Results: The application of 3 mg/L DS decreased the frequency of sponta- neous and synchronous oscillations of intracellular Ca2+ to 72%±2% (mean±SEM), and the spontaneous inhibitory postsynaptic currents to 60%±3% (mean±SEM). The inhibitory concentraton 50% (IC50) for the effect of DS on calcium oscillations was 3.8 mg/L. DS also depressed the high voltage-gated Ca2+ channel and the voltage-gated Na+ channel currents at the same time point. It had no effect, however, on voltage-gated K+ and spontaneous excitatory postsynaptic currents. Conclusion: DS inhibited the spontaneous and synchronous oscillations of intra- cellular Ca2+ through the depression of influx of extracellular calcium and the initiation of action potential. By repressing the spontaneous neurotransmitter release, DS modulated the neuronal network activities.

  2. TRPM4-dependent post-synaptic depolarization is essential for the induction of NMDA receptor-dependent LTP in CA1 hippocampal neurons.

    Science.gov (United States)

    Menigoz, Aurélie; Ahmed, Tariq; Sabanov, Victor; Philippaert, Koenraad; Pinto, Silvia; Kerselaers, Sara; Segal, Andrei; Freichel, Marc; Voets, Thomas; Nilius, Bernd; Vennekens, Rudi; Balschun, Detlef

    2016-04-01

    TRPM4 is a calcium-activated but calcium-impermeable non-selective cation (CAN) channel. Previous studies have shown that TRPM4 is an important regulator of Ca(2+)-dependent changes in membrane potential in excitable and non-excitable cell types. However, its physiological significance in neurons of the central nervous system remained unclear. Here, we report that TRPM4 proteins form a CAN channel in CA1 neurons of the hippocampus and we show that TRPM4 is an essential co-activator of N-methyl-D-aspartate (NMDA) receptors (NMDAR) during the induction of long-term potentiation (LTP). Disrupting the Trpm4 gene in mice specifically eliminates NMDAR-dependent LTP, while basal synaptic transmission, short-term plasticity, and NMDAR-dependent long-term depression are unchanged. The induction of LTP in Trpm4 (-/-) neurons was rescued by facilitating NMDA receptor activation or post-synaptic membrane depolarization. Accordingly, we obtained normal LTP in Trpm4 (-/-) neurons in a pairing protocol, where post-synaptic depolarization was applied in parallel to pre-synaptic stimulation. Taken together, our data are consistent with a novel model of LTP induction in CA1 hippocampal neurons, in which TRPM4 is an essential player in a feed-forward loop that generates the post-synaptic membrane depolarization which is necessary to fully activate NMDA receptors during the induction of LTP but which is dispensable for the induction of long-term depression (LTD). These results have important implications for the understanding of the induction process of LTP and the development of nootropic medication. PMID:26631168

  3. How Ca2+-permeable AMPA receptors, the kinase PKA, and the phosphatase PP2B are intertwined in synaptic LTP and LTD.

    Science.gov (United States)

    Hell, Johannes W

    2016-04-26

    Both synaptic long-term potentiation (LTP) and long-term depression (LTD) are thought to be critical for memory formation. Dell'Acqua and co-workers now demonstrate that transient postsynaptic incorporation of Ca(2+)-permeable (CP) α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) is required for LTD in the exemplary hippocampal CA1 region in 2-week-old mice. Mechanistically, LTD depends on AKAP150-anchored protein kinase A (PKA) to promote the initial functional recruitment of CP-AMPARs during LTD induction and on AKAP150-anchored protein phosphatase 2B (PP2B) to trigger their subsequent removal as part of the lasting depression of synaptic transmission.

  4. Sulforhodamine 101 induces long-term potentiation of intrinsic excitability and synaptic efficacy in hippocampal CA1 pyramidal neurons

    DEFF Research Database (Denmark)

    Kang, J.; Kang, N.; Yu, Y.;

    2010-01-01

    . The N-methyl D-aspartate receptor (NMDAR) antagonist, AP-5 (50 microM), blocked SR101-induced LTP-IE, but glutamate receptor blockers, AP-5 (50 microM), MCPG (200 microM), and MSOP (100 microM), only partially blocked SR101-induced potentiation of eEPSCs. SR101 induced an enhancement of evoked synaptic...... NMDAR currents, suggesting that SR101 enhances activation of synaptic NMDARs. SR101-induced LTP-IE and potentiation of synaptic transmission triggered spontaneous neuronal firing in slices and in vivo epileptic seizures. Our results suggest that SR101 is an epileptogenic agent that long-lastingly lowers...... the AP threshold to increase intrinsic neuronal excitability and enhances the synaptic efficacy to increase synaptic inputs. As such, SR101 can be used as an experimental tool to induce epileptic seizures....

  5. Apolipoprotein E4 impairs in vivo hippocampal long-term synaptic plasticity by reducing the phosphorylation of CaMKIIα and CREB.

    Science.gov (United States)

    Qiao, Feng; Gao, Xiu-Ping; Yuan, Li; Cai, Hong-Yan; Qi, Jin-Shun

    2014-01-01

    Inheritance of the apolipoprotein E genotype ε4 (APOE4) is a powerful risk factor for most cases of late-onset Alzheimer's disease (AD). However, the effects of ApoE4 on the long-term synaptic plasticity and its underlying mechanism have not clearly investigated. In the present study, we examined the effects of ApoE4 on the hippocampal late-phase long-term potentiation (L-LTP) and investigated its probable molecular mechanisms by using in vivo field potential recording, immunohistochemistry, and western blotting. The results showed that: (1) intra-hippocampal injection of 0.2 μg ApoE4, but not ApoE2, before high frequency stimulations (HFSs) attenuated the induction of hippocampal L-LTP in the CA1 region, while injection of the same concentration of ApoE4 after HFSs, even at a higher concentration (2 μg), did not affect the long term synaptic plasticity; (2) ApoE4 injection did not affect the paired pulse facilitation in the hippocampal CA1 region; (3) ApoE4 injection before, not after, HFSs significantly decreased the levels of phosphorylated Ca2+/calmodulin-dependent protein kinase IIα (p-CaMKIIα) and phosphorylated cAMP response element-binding protein (p-CREB) in the hippocampus. These results demonstrated for the first time that ApoE4 could impair hippocampal L-LTP by reducing p-CaMKIIα and p-CREB, suggesting that the ApoE4-induced suppression of hippocampal long-term synaptic plasticity may contribute to the cognitive impairments in genetic AD; and both CaMKIIα and CREB are important intracellular targets of the neurotoxic ApoE4.

  6. Effects of movement training on synaptic interface structure in the sensorimotor cortex and hippocampal CA3 area of the ischemic hemisphere in cerebral infarction rats

    Institute of Scientific and Technical Information of China (English)

    Min Yang; Jiyan Cheng

    2008-01-01

    BACKGROUND: Movement is an effective way to provide sensory, movement and reflectivity afferent stimulation to the central nervous system. Movement plays an important role in functional recombination and compensation in the brain. OBJECTIVE: To observe movement training effects on texture parameters of synaptic interfaces in the sensorimotor cortex and hippocampal CA3 area of the ischemic hemisphere and on motor function in cerebral infarction rats. DESIGN, TIME AND SETTING: This neural morphology and pathology randomized controlled animal experiment was performed at the Center Laboratory, Affiliated Hospital of Luzhou Medical College, China from November 2004 to April 2005. MATERIALS: A total of 32 healthy male Wistar rats aged 8 weeks were equally and randomly assigned into model and movement training groups. METHODS: Rat models of right middle cerebral artery occlusion were established using the suture occlusion method in both groups. Rats in the movement training group underwent balance training, screen training, and rotating rod training starting on day 5 after surgery, for 40 minutes every day, 6 days per week, for 4 weeks. MAIN OUTCOME MEASURES: Texture parameters of synaptic interfaces were determined using a transmission electron microscope and image analyzer during week 5 following model induction. The following parameters were measured: synaptic cleft width; postsynaptic density thickness; synaptic interface curvature; and active zone length. Motor function was assessed using balance training, screen training, and rotating rod training. The lower score indicated a better motor function. RESULTS: The postsynaptic density thickness, synaptic interface curvature, and active zone length were significantly increased in the sensorimotor cortex and hippocampal CA3 area of the ischemic hemisphere of rats from the movement training group compared with the model group (P < 0.05 or 0.01). Curved synapses and perforated synapses were seen in the sensorimotor cortex

  7. Propofol ameliorates electroconvulsive shock-induced learning and memory impairment by regulation of synaptic metaplasticity via autophosphorylation of CaMKIIa at Thr 305 in stressed rats.

    Science.gov (United States)

    Ren, Li; Zhang, Fan; Min, Su; Hao, Xuechao; Qin, Peipei; Zhu, Xianlin

    2016-06-30

    Electroconvulsive therapy (ECT) is an effective treatment for depression, but it can induce learning and memory impairment. Our previous study found propofol (γ-aminobutyric acid (GABA) receptor agonist) could ameliorate electroconvulsive shock (ECS, an analog of ECT to animals)-induced cognitive impairment, however, the underlying molecular mechanisms remain unclear. This study aimed to investigate the effects of propofol on metaplasticity and autophosphorylation of CaMKIIa in stressed rats receiving ECS. Depressive-like behavior and learning and memory function were assessed by sucrose preference test and Morris water test respectively. LTP were tested by electrophysiological experiment, the expression of CaMKIIa, p-T305-CaMKII in hippocampus and CaMKIIα in hippocampal PSD fraction were evaluated by western blot. Results suggested ECS raised the baseline fEPSP and impaired the subsequent LTP, increased the expression of p-T305-CaMKII and decreased the expression of CaMKIIα in hippocampal PSD fraction, leading to cognitive dysfunction in stressed rats. Propofol could down-regulate the baseline fEPSP and reversed the impairment of LTP partly, decreased the expression of p-T305-CaMKII and increased the expression of CaMKIIα in hippocampal PSD fraction and alleviated ECS-induced learning and memory impairment. In conclusion, propofol ameliorates ECS-induced learning and memory impairment, possibly by regulation of synaptic metaplasticity via p-T305-CaMKII. PMID:27104927

  8. Impairment of L-type Ca2+ channel-dependent forms of hippocampal synaptic plasticity in mice deficient in the extracellular matrix glycoprotein tenascin-C.

    Science.gov (United States)

    Evers, Matthias R; Salmen, Benedikt; Bukalo, Olena; Rollenhagen, Astrid; Bösl, Michael R; Morellini, Fabio; Bartsch, Udo; Dityatev, Alexander; Schachner, Melitta

    2002-08-15

    The extracellular matrix glycoprotein tenascin-C (TN-C) has been suggested to play important functional roles during neural development, axonal regeneration, and synaptic plasticity. We generated a constitutively TN-C-deficient mouse mutant from embryonic stem cells with a floxed tn-C allele, representing a standard for future analysis of conditionally targeted mice. The gross morphology of the CNS was not detectably affected, including no evidence for perturbed nerve cell migration, abnormal oligodendrocyte distribution, or defective myelination. Despite the apparent normal histology of the hippocampus and normal performance in the water maze, theta-burst stimulation (TBS) of Schaffer collaterals elicited reduced long-term potentiation (LTP) in the CA1 region of TN-C-deficient mutants, as compared with wild-type littermates. However, high-frequency stimulation evoked normal LTP not only in CA1, but also at mossy fiber-CA3 and medial and lateral perforant path-granule cell synapses in the dentate gyrus. Low-frequency stimulation failed to induce long-term depression in the CA1 region of TN-C-deficient animals. Recordings of TBS-induced LTP in the presence of nifedipine, an antagonist of L-type voltage-dependent Ca2+ channels (VDCCs), did not affect LTP in TN-C-deficient mice, but reduced LTP in wild-type mice to the levels seen in mutants. Furthermore, chemical induction of a L-type VDCC-dependent LTP in the CA1 region by application of the K+ channel blocker tetraethylammonium resulted in impaired LTP in TN-C mutants. Thus, reduction in L-type VDCC-mediated signaling appears to mediate the deficits in certain forms of synaptic plasticity in constitutively TN-C-deficient mice. PMID:12177213

  9. Different Compartments of Apical CA1 Dendrites Have Different Plasticity Thresholds for Expressing Synaptic Tagging and Capture

    Science.gov (United States)

    Sajikumar, Sreedharan; Korte, Martin

    2011-01-01

    The consolidation process from short- to long-term memory depends on the type of stimulation received from a specific neuronal network and on the cooperativity and associativity between different synaptic inputs converging onto a specific neuron. We show here that the plasticity thresholds for inducing LTP are different in proximal and distal…

  10. Mechanism underlying unaltered cortical inhibitory synaptic transmission in contrast with enhanced excitatory transmission in CaV2.1 knockin migraine mice.

    Science.gov (United States)

    Vecchia, Dania; Tottene, Angelita; van den Maagdenberg, Arn M J M; Pietrobon, Daniela

    2014-09-01

    Familial hemiplegic migraine type 1 (FHM1), a monogenic subtype of migraine with aura, is caused by gain-of-function mutations in CaV2.1 (P/Q-type) calcium channels. In FHM1 knockin mice, excitatory neurotransmission at cortical pyramidal cell synapses is enhanced, but inhibitory neurotransmission at connected pairs of fast-spiking (FS) interneurons and pyramidal cells is unaltered, despite being initiated by CaV2.1 channels. The mechanism underlying the unaltered GABA release at cortical FS interneuron synapses remains unknown. Here, we show that the FHM1 R192Q mutation does not affect inhibitory transmission at autapses of cortical FS and other types of multipolar interneurons in microculture from R192Q knockin mice, and investigate the underlying mechanism. Lowering the extracellular [Ca(2+)] did not reveal gain-of-function of evoked transmission neither in control nor after prolongation of the action potential (AP) with tetraethylammonium, indicating unaltered AP-evoked presynaptic calcium influx at inhibitory autapses in FHM1 KI mice. Neither saturation of the presynaptic calcium sensor nor short duration of the AP can explain the unaltered inhibitory transmission in the mutant mice. Recordings of the P/Q-type calcium current in multipolar interneurons in microculture revealed that the current density and the gating properties of the CaV2.1 channels expressed in these interneurons are barely affected by the FHM1 mutation, in contrast with the enhanced current density and left-shifted activation gating of mutant CaV2.1 channels in cortical pyramidal cells. Our findings suggest that expression of specific CaV2.1 channels differentially sensitive to modulation by FHM1 mutations in inhibitory and excitatory cortical neurons underlies the gain-of-function of excitatory but unaltered inhibitory synaptic transmission and the likely consequent dysregulation of the cortical excitatory-inhibitory balance in FHM1. PMID:24907493

  11. The effects of NR2 subunit-dependent NMDA receptor kinetics on synaptic transmission and CaMKII activation.

    Directory of Open Access Journals (Sweden)

    David M Santucci

    2008-10-01

    Full Text Available N-Methyl-D-aspartic acid (NMDA receptors are widely expressed in the brain and are critical for many forms of synaptic plasticity. Subtypes of the NMDA receptor NR2 subunit are differentially expressed during development; in the forebrain, the NR2B receptor is dominant early in development, and later both NR2A and NR2B are expressed. In heterologous expression systems, NR2A-containing receptors open more reliably and show much faster opening and closing kinetics than do NR2B-containing receptors. However, conflicting data, showing similar open probabilities, exist for receptors expressed in neurons. Similarly, studies of synaptic plasticity have produced divergent results, with some showing that only NR2A-containing receptors can drive long-term potentiation and others showing that either subtype is capable of driving potentiation. In order to address these conflicting results as well as open questions about the number and location of functional receptors in the synapse, we constructed a Monte Carlo model of glutamate release, diffusion, and binding to NMDA receptors and of receptor opening and closing as well as a model of the activation of calcium-calmodulin kinase II, an enzyme critical for induction of synaptic plasticity, by NMDA receptor-mediated calcium influx. Our results suggest that the conflicting data concerning receptor open probabilities can be resolved, with NR2A- and NR2B-containing receptors having very different opening probabilities. They also support the conclusion that receptors containing either subtype can drive long-term potentiation. We also are able to estimate the number of functional receptors at a synapse from experimental data. Finally, in our models, the opening of NR2B-containing receptors is highly dependent on the location of the receptor relative to the site of glutamate release whereas the opening of NR2A-containing receptors is not. These results help to clarify the previous findings and suggest future

  12. Enhanced Glutamatergic Synaptic Plasticity in the Hippocampal CA1 Field of Food-Restricted Rats: Involvement of CB1 Receptors.

    Science.gov (United States)

    Talani, Giuseppe; Licheri, Valentina; Biggio, Francesca; Locci, Valentina; Mostallino, Maria Cristina; Secci, Pietro Paolo; Melis, Valentina; Dazzi, Laura; Carta, Gianfranca; Banni, Sebastiano; Biggio, Giovanni; Sanna, Enrico

    2016-04-01

    The endogenous endocannabinoid system has a crucial role in regulating appetite and feeding behavior in mammals, as well as working memory and reward mechanisms. In order to elucidate the possible role of cannabinoid type-1 receptors (CB1Rs) in the regulation of hippocampal plasticity in animals exposed to food restriction (FR), we limited the availability of food to a 2-h daily period for 3 weeks in Sprague-Dawley rats. FR rats showed a higher long-term potentiation at hippocampal CA1 excitatory synapses with a parallel increase in glutamate release when compared with animals fed ad libitum. FR rats showed a significant increase in the long-term spatial memory determined by Barnes maze. FR was also associated with a decreased inhibitory effect of the CB1R agonist win55,212-2 on glutamatergic field excitatory postsynaptic potentials, together with a decrease in hippocampal CB1R protein expression. In addition, hippocampal brain-derived neurotrophic factor protein levels and mushroom dendritic spine density were significantly enhanced in FR rats. Altogether, our data suggest that alterations of hippocampal CB1R expression and function in FR rats are associated with dendritic spine remodeling and functional potentiation of CA1 excitatory synapses, and these findings are consistent with increasing evidence supporting the idea that FR may improve cognitive functions.

  13. 术中机械通气对小鼠海马CA1区突触可塑性的影响%Effect of mechanical ventilation on synaptic plasticity in hippocampal CA1 region of mice

    Institute of Scientific and Technical Information of China (English)

    陈婷; 张宗泽; 陈畅; 彭勉; 许鑫; 陈凯; 王焱林

    2015-01-01

    目的 评价术中机械通气对小鼠海马CA1区突触可塑性的影响.方法 健康雄性C57BL/6小鼠36只,8~10周龄,体重20~25 g,采用随机数字表法,将其分成2组(n=18):对照组(C组)和机械通气组(M组).小鼠在麻醉后气管插管并行胫骨骨折切开复位内固定术.C组术后拔除气管导管,放入麻醉箱6h,通入1.5%异氟醚维持麻醉;M组术后继续机械通气6h,吸入1.5%异氟醚维持麻醉.于机械通气结束后2h、1和3d时,取6只小鼠进行恐惧条件化实验,记录僵直时间百分比.于机械通气结束后1d时取6只小鼠开始进行新物体识别实验,第4天时间隔5 min、2h和1d时,计算优先指数.于机械通气结束后1d时处死3只小鼠,取海马组织,电镜下观察海马超微结构,并记录突触数量.于机械通气结束后1d时处死3只小鼠,取全脑组织,进行高尔基染色,测定树突棘密度.结果 与C组比较,M组术后2h和1d时僵直时间百分比降低,不同时间间隔优先指数降低,海马CA1区突触数量减少,顶树突棘密度和基树突棘密度降低(P<0.01).结论 术中机械通气可改变小鼠海马CA1区突触可塑性.%Objective To evaluate the effect of mechanical ventilation on synaptic plasticity in hippocampal CA1 region of mice.Methods Thirty-six male C57BL/6 mice,aged 8-10 weeks,weighing 20-25 g,were randomly divided into 2 groups (n =18 each) using a random number table:control group (group C) and mechanical ventilation group (group M).After anesthesia,endotracheal intubation was carried out,and open reduction and internal fixation was performed after tibial fracture was induced in mice.In C group,the endotracheal tube was removed after operation,and then the mice were exposed to 1.5% isoflurane for 6 h in a chamber.In M group,the mice were mechanically ventilated continuously for 6 h,and 1.5% isoflurane was inhaled to maintain the level of anesthesia.At 2 h and 1 and 3 days after the end of ventilation,6 mice were

  14. Synaptic conditions for auto-associative memory storage and pattern completion in Jensen et al.'s model of hippocampal area CA3.

    Science.gov (United States)

    Cheu, Eng Yeow; Yu, Jiali; Tan, Chin Hiong; Tang, Huajin

    2012-12-01

    Jensen et al. (Learn Memory 3(2-3):243-256, 1996b) proposed an auto-associative memory model using an integrated short-term memory (STM) and long-term memory (LTM) spiking neural network. Their model requires that distinct pyramidal cells encoding different STM patterns are fired in different high-frequency gamma subcycles within each low-frequency theta oscillation. Auto-associative LTM is formed by modifying the recurrent synaptic efficacy between pyramidal cells. In order to store auto-associative LTM correctly, the recurrent synaptic efficacy must be bounded. The synaptic efficacy must be upper bounded to prevent re-firing of pyramidal cells in subsequent gamma subcycles. If cells encoding one memory item were to re-fire synchronously with other cells encoding another item in subsequent gamma subcycle, LTM stored via modifiable recurrent synapses would be corrupted. The synaptic efficacy must also be lower bounded so that memory pattern completion can be performed correctly. This paper uses the original model by Jensen et al. as the basis to illustrate the following points. Firstly, the importance of coordinated long-term memory (LTM) synaptic modification. Secondly, the use of a generic mathematical formulation (spiking response model) that can theoretically extend the results to other spiking network utilizing threshold-fire spiking neuron model. Thirdly, the interaction of long-term and short-term memory networks that possibly explains the asymmetric distribution of spike density in theta cycle through the merger of STM patterns with interaction of LTM network.

  15. Spontaneous Vesicle Recycling in the Synaptic Bouton

    Directory of Open Access Journals (Sweden)

    Sven eTruckenbrodt

    2014-12-01

    Full Text Available The trigger for synaptic vesicle exocytosis is Ca2+, which enters the synaptic bouton following action potential stimulation. However, spontaneous release of neurotransmitter also occurs in the absence of stimulation in virtually all synaptic boutons. It has long been thought that this represents exocytosis driven by fluctuations in local Ca2+ levels. The vesicles responding to these fluctuations are thought to be the same ones that release upon stimulation, albeit potentially triggered by different Ca2+ sensors. This view has been challenged by several recent works, which have suggested that spontaneous release is driven by a separate pool of synaptic vesicles. Numerous articles appeared during the last few years in support of each of these hypotheses, and it has been challenging to bring them into accord. We speculate here on the origins of this controversy, and propose a solution that is related to developmental effects. Constitutive membrane traffic, needed for the biogenesis of vesicles and synapses, is responsible for high levels of spontaneous membrane fusion in young neurons, probably independent of Ca2+. The vesicles releasing spontaneously in such neurons are not related to other synaptic vesicle pools and may represent constitutively releasing vesicles (CRVs rather than bona fide synaptic vesicles. In mature neurons, constitutive traffic is much dampened, and the few remaining spontaneous release events probably represent bona fide spontaneously releasing synaptic vesicles (SRSVs responding to Ca2+ fluctuations, along with a handful of CRVs that participate in synaptic vesicle turnover.

  16. Spontaneous vesicle recycling in the synaptic bouton.

    Science.gov (United States)

    Truckenbrodt, Sven; Rizzoli, Silvio O

    2014-01-01

    The trigger for synaptic vesicle exocytosis is Ca(2+), which enters the synaptic bouton following action potential stimulation. However, spontaneous release of neurotransmitter also occurs in the absence of stimulation in virtually all synaptic boutons. It has long been thought that this represents exocytosis driven by fluctuations in local Ca(2+) levels. The vesicles responding to these fluctuations are thought to be the same ones that release upon stimulation, albeit potentially triggered by different Ca(2+) sensors. This view has been challenged by several recent works, which have suggested that spontaneous release is driven by a separate pool of synaptic vesicles. Numerous articles appeared during the last few years in support of each of these hypotheses, and it has been challenging to bring them into accord. We speculate here on the origins of this controversy, and propose a solution that is related to developmental effects. Constitutive membrane traffic, needed for the biogenesis of vesicles and synapses, is responsible for high levels of spontaneous membrane fusion in young neurons, probably independent of Ca(2+). The vesicles releasing spontaneously in such neurons are not related to other synaptic vesicle pools and may represent constitutively releasing vesicles (CRVs) rather than bona fide synaptic vesicles. In mature neurons, constitutive traffic is much dampened, and the few remaining spontaneous release events probably represent bona fide spontaneously releasing synaptic vesicles (SRSVs) responding to Ca(2+) fluctuations, along with a handful of CRVs that participate in synaptic vesicle turnover.

  17. Cortical synaptic transmission in CaV2.1 knockin mice with the S218L missense mutation which causes a severe familial hemiplegic migraine syndrome in humans.

    Directory of Open Access Journals (Sweden)

    Dania eVecchia

    2015-02-01

    Full Text Available Familial hemiplegic migraine type 1 (FHM1 is caused by gain-of-function mutations in CaV2.1 (P/Q-type Ca2+ channels. Knockin (KI mice carrying the FHM1 R192Q missense mutation show enhanced cortical excitatory synaptic transmission at pyramidal cell synapses but unaltered cortical inhibitory neurotransmission at fast-spiking interneuron synapses. Enhanced cortical glutamate release was shown to cause the facilitation of cortical spreading depression (CSD in R192Q KI mice. It, however, remains unknown how other FHM1 mutations affect cortical synaptic transmission. Here, we studied neurotransmission in cortical neurons in microculture from KI mice carrying the S218L mutation, which causes a severe FHM syndrome in humans and an allele-dosage dependent facilitation of experimental CSD in KI mice, which is larger than that caused by the R192Q mutation. We show gain-of-function of excitatory neurotransmission, due to increased action-potential evoked Ca2+ influx and increased probability of glutamate release at pyramidal cell synapses, but unaltered inhibitory neurotransmission at multipolar interneuron synapses in S218L KI mice. In contrast with the larger gain-of-function of neuronal CaV2.1 current in homozygous than heterozygous S218L KI mice, the gain-of-function of evoked glutamate release, the paired-pulse ratio and the Ca2+ dependence of the EPSC were all similar in homozygous and heterozygous S218L KI mice, suggesting compensatory changes in the homozygous mice. Furthermore, we reveal a unique feature of S218L KI cortical synapses which is the presence of a fraction of mutant CaV2.1 channels being open at resting potential. Our data suggest that, while the gain-of-function of evoked glutamate release may explain the facilitation of CSD in heterozygous S218L KI mice, the further facilitation of CSD in homozygous S218L KI mice is due to other CaV2.1-dependent mechanisms, that likely include Ca2+ influx at voltages sub-threshold for action

  18. Abnormal cortical synaptic transmission in CaV2.1 knockin mice with the S218L missense mutation which causes a severe familial hemiplegic migraine syndrome in humans.

    Science.gov (United States)

    Vecchia, Dania; Tottene, Angelita; van den Maagdenberg, Arn M J M; Pietrobon, Daniela

    2015-01-01

    Familial hemiplegic migraine type 1 (FHM1) is caused by gain-of-function mutations in CaV2.1 (P/Q-type) Ca(2+) channels. Knockin (KI) mice carrying the FHM1 R192Q missense mutation show enhanced cortical excitatory synaptic transmission at pyramidal cell synapses but unaltered cortical inhibitory neurotransmission at fast-spiking interneuron synapses. Enhanced cortical glutamate release was shown to cause the facilitation of cortical spreading depression (CSD) in R192Q KI mice. It, however, remains unknown how other FHM1 mutations affect cortical synaptic transmission. Here, we studied neurotransmission in cortical neurons in microculture from KI mice carrying the S218L mutation, which causes a severe FHM syndrome in humans and an allele-dosage dependent facilitation of experimental CSD in KI mice, which is larger than that caused by the R192Q mutation. We show gain-of-function of excitatory neurotransmission, due to increased action-potential evoked Ca(2+) influx and increased probability of glutamate release at pyramidal cell synapses, but unaltered inhibitory neurotransmission at multipolar interneuron synapses in S218L KI mice. In contrast with the larger gain-of-function of neuronal CaV2.1 current in homozygous than heterozygous S218L KI mice, the gain-of-function of evoked glutamate release, the paired-pulse ratio and the Ca(2+) dependence of the excitatory postsynaptic current were similar in homozygous and heterozygous S218L KI mice, suggesting compensatory changes in the homozygous mice. Furthermore, we reveal a unique feature of S218L KI cortical synapses which is the presence of a fraction of mutant CaV2.1 channels being open at resting potential. Our data suggest that, while the gain-of-function of evoked glutamate release may explain the facilitation of CSD in heterozygous S218L KI mice, the further facilitation of CSD in homozygous S218L KI mice is due to other CaV2.1-dependent mechanisms, that likely include Ca(2+) influx at voltages sub

  19. Data-Driven Modeling of Synaptic Transmission and Integration

    OpenAIRE

    Rothman, Jason S.; Silver, R. Angus

    2014-01-01

    In this chapter, we describe how to create mathematical models of synaptic transmission and integration. We start with a brief synopsis of the experimental evidence underlying our current understanding of synaptic transmission. We then describe synaptic transmission at a particular glutamatergic synapse in the mammalian cerebellum, the mossy fiber to granule cell synapse, since data from this well-characterized synapse can provide a benchmark comparison for how well synaptic properties are ca...

  20. GABAA Receptor-Mediated Bidirectional Control of Synaptic Activity, Intracellular Ca2+, Cerebral Blood Flow, and Oxygen Consumption in Mouse Somatosensory Cortex In Vivo

    DEFF Research Database (Denmark)

    Jessen, Sanne Barsballe; Brazhe, Alexey; Lind, Barbara Lykke;

    2015-01-01

    concentrations of THIP suppressed ΔCBF and ΔCMRO2 at high stimulation frequencies. Zolpidem had similar but less-pronounced effects, with similar dependence on drug concentration and stimulation frequency. Our present findings suggest that slight increases in both synaptic and extrasynaptic GABAAR activity might......Neural activity regulates local increases in cerebral blood flow (ΔCBF) and the cortical metabolic rate of oxygen (ΔCMRO2) that constitutes the basis of BOLD functional neuroimaging signals. Glutamate signaling plays a key role in brain vascular and metabolic control; however, the modulatory effect...

  1. EDITORIAL: Synaptic electronics Synaptic electronics

    Science.gov (United States)

    Demming, Anna; Gimzewski, James K.; Vuillaume, Dominique

    2013-09-01

    Conventional computers excel in logic and accurate scientific calculations but make hard work of open ended problems that human brains handle easily. Even von Neumann—the mathematician and polymath who first developed the programming architecture that forms the basis of today's computers—was already looking to the brain for future developments before his death in 1957 [1]. Neuromorphic computing uses approaches that better mimic the working of the human brain. Recent developments in nanotechnology are now providing structures with very accommodating properties for neuromorphic approaches. This special issue, with guest editors James K Gimzewski and Dominique Vuillaume, is devoted to research at the serendipitous interface between the two disciplines. 'Synaptic electronics', looks at artificial devices with connections that demonstrate behaviour similar to synapses in the nervous system allowing a new and more powerful approach to computing. Synapses and connecting neurons respond differently to incident signals depending on the history of signals previously experienced, ultimately leading to short term and long term memory behaviour. The basic characteristics of a synapse can be replicated with around ten simple transistors. However with the human brain having around 1011 neurons and 1015 synapses, artificial neurons and synapses from basic transistors are unlikely to accommodate the scalability required. The discovery of nanoscale elements that function as 'memristors' has provided a key tool for the implementation of synaptic connections [2]. Leon Chua first developed the concept of the 'The memristor—the missing circuit element' in 1971 [3]. In this special issue he presents a tutorial describing how memristor research has fed into our understanding of synaptic behaviour and how they can be applied in information processing [4]. He also describes, 'The new principle of local activity, which uncovers a minuscule life-enabling "Goldilocks zone", dubbed the

  2. EDITORIAL: Synaptic electronics Synaptic electronics

    Science.gov (United States)

    Demming, Anna; Gimzewski, James K.; Vuillaume, Dominique

    2013-09-01

    Conventional computers excel in logic and accurate scientific calculations but make hard work of open ended problems that human brains handle easily. Even von Neumann—the mathematician and polymath who first developed the programming architecture that forms the basis of today's computers—was already looking to the brain for future developments before his death in 1957 [1]. Neuromorphic computing uses approaches that better mimic the working of the human brain. Recent developments in nanotechnology are now providing structures with very accommodating properties for neuromorphic approaches. This special issue, with guest editors James K Gimzewski and Dominique Vuillaume, is devoted to research at the serendipitous interface between the two disciplines. 'Synaptic electronics', looks at artificial devices with connections that demonstrate behaviour similar to synapses in the nervous system allowing a new and more powerful approach to computing. Synapses and connecting neurons respond differently to incident signals depending on the history of signals previously experienced, ultimately leading to short term and long term memory behaviour. The basic characteristics of a synapse can be replicated with around ten simple transistors. However with the human brain having around 1011 neurons and 1015 synapses, artificial neurons and synapses from basic transistors are unlikely to accommodate the scalability required. The discovery of nanoscale elements that function as 'memristors' has provided a key tool for the implementation of synaptic connections [2]. Leon Chua first developed the concept of the 'The memristor—the missing circuit element' in 1971 [3]. In this special issue he presents a tutorial describing how memristor research has fed into our understanding of synaptic behaviour and how they can be applied in information processing [4]. He also describes, 'The new principle of local activity, which uncovers a minuscule life-enabling "Goldilocks zone", dubbed the

  3. Classification: Molecular & Synaptic Mechanisms

    Science.gov (United States)

    Lussier, Marc P.; Gu, Xinglong; Lu, Wei; Roche, Katherine W.

    2014-01-01

    Controlling the density of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) at synapses is essential for regulating the strength of excitatory neurotransmission. In particular, the phosphorylation of AMPARs is important for defining both synaptic expression and intracellular routing of receptors. Phosphorylation is a posttranslational modification known to regulate many cellular events and the C-termini of glutamate receptors are important targets. Recently, the first intracellular loop1 region of the GluA1 subunit of AMPARs was reported to regulate synaptic targeting through phosphorylation of S567 by Ca2+/calmodulin-dependent protein kinase II (CaMKII). Intriguingly, the loop1 region of all four AMPAR subunits contains many putative phosphorylation sites (S/T/Y), leaving the possibility that other kinases may regulate AMPAR surface expression via phosphorylation of the loop regions. To explore this hypothesis, we used in vitro phosphorylation assays with a small panel of purified kinases and found that casein kinase 2 (CK2) phosphorylates the GluA1 and GluA2 loop1 regions, but not GluA3 or GluA4. Interestingly, when we reduced the endogenous expression of CK2 using a specific shRNA against the regulatory subunit CK2β, we detected a reduction of GluA1 surface expression, whereas GluA2 was unchanged. Furthermore, we identified S579 of GluA1 as a substrate of CK2, and the expression of GluA1 phospho-deficient mutants in hippocampal neurons displayed reduced surface expression. Therefore, our study identifies CK2 as a regulator of GluA1 surface expression by phosphorylating the intracellular loop1 region. PMID:24712994

  4. 8-[2-(2-pentyl-cyclopropylmethyl)-cyclopropyl]-octanoic acid stimulates GABA release from interneurons projecting to CA1 pyramidal neurons in the rat hippocampus via pre-synaptic alpha7 acetylcholine receptors.

    Science.gov (United States)

    Kanno, Takeshi; Yaguchi, Takahiro; Yamamoto, Satoshi; Yamamoto, Hideyuki; Fujikawa, Hirokazu; Nagata, Tetsu; Tanaka, Akito; Nishizaki, Tomoyuki

    2005-11-01

    Nicotinic acetylcholine (ACh) receptors, such as alpha7, alpha3beta4 and alpha4beta2 receptors in the hippocampus, are suggested to modulate neurotransmitter release. 8-[2-(2-Pentyl-cyclopropylmethyl)-cyclopropyl]-octanoic acid (DCP-LA) (100 nM), a linoleic acid derivative, potentiated responses of alpha7, alpha3beta4 and alpha4beta2 ACh receptors expressed in Xenopus oocytes that are blocked by 3-(1-[dimethylaminopropyl] indol-3-yl)-4-[indol-3-yl] maleimide (GF109203X), a selective inhibitor of protein kinase C (PKC), except for alpha3beta4 ACh receptors. DCP-LA enhanced the nicotine-triggered release of GABA from rat hippocampal slices in the presence of tetrodotoxin in a bell-shaped dose-dependent manner at concentrations ranging from 10 nM to 10 microM, although DCP-LA by itself had no effect on GABA release. The DCP-LA action was inhibited by GF109203X or alpha-bungarotoxin, an inhibitor of alpha7 ACh receptors, but not by mecamylamine or dihydro-beta-erithroidine, an inhibitor of alpha3beta4 and alpha4beta2 ACh receptors. A similar effect on GABA release was obtained with 12-O-tetradecanoylphorbol 13-acetate, a PKC activator. DCP-LA (100 nM) also enhanced GABA release triggered by choline, an agonist of alpha7 ACh receptors, but not 3-[2(s)-azetidinylmethoxy] pyridine, an agonist of alpha4beta2 ACh receptors. In addition, DCP-LA (100 nM) increased the rate of nicotine-triggered GABA(A) receptor-mediated miniature inhibitory post-synaptic currents, monitored from CA1 pyramidal neurons of rat hippocampal slices, and the effect was also inhibited by GF109203X or alpha-bungarotoxin but not by mecamylamine. Thus, the results of the present study indicate that DCP-LA stimulates GABA release by enhancing activity of pre-synaptic alpha7 ACh receptors present on the GABAergic terminals of interneurons that transmit to CA1 pyramidal neurons via a PKC pathway. PMID:16248884

  5. Acute stress causes rapid synaptic insertion of Ca2+ -permeable AMPA receptors to facilitate long-term potentiation in the hippocampus.

    Science.gov (United States)

    Whitehead, Garry; Jo, Jihoon; Hogg, Ellen L; Piers, Thomas; Kim, Dong-Hyun; Seaton, Gillian; Seok, Heon; Bru-Mercier, Gilles; Son, Gi Hoon; Regan, Philip; Hildebrandt, Lars; Waite, Eleanor; Kim, Byeong-Chae; Kerrigan, Talitha L; Kim, Kyungjin; Whitcomb, Daniel J; Collingridge, Graham L; Lightman, Stafford L; Cho, Kwangwook

    2013-12-01

    The neuroendocrine response to episodes of acute stress is crucial for survival whereas the prolonged response to chronic stress can be detrimental. Learning and memory are particularly susceptible to stress with cognitive deficits being well characterized consequences of chronic stress. Although there is good evidence that acute stress can enhance cognitive performance, the mechanism(s) for this are unclear. We find that hippocampal slices, either prepared from rats following 30 min restraint stress or directly exposed to glucocorticoids, exhibit an N-methyl-d-aspartic acid receptor-independent form of long-term potentiation. We demonstrate that the mechanism involves an NMDA receptor and PKA-dependent insertion of Ca2+ -permeable AMPA receptors into synapses. These then trigger the additional NMDA receptor-independent form of LTP during high frequency stimulation.

  6. Third Trimester Equivalent Alcohol Exposure Reduces Modulation of Glutamatergic Synaptic Transmission by 5-HT1A Receptors in the Rat Hippocampal CA3 Region

    Science.gov (United States)

    Morton, Russell A.; Valenzuela, C. Fernando

    2016-01-01

    Fetal alcohol exposure has been associated with many neuropsychiatric disorders that have been linked to altered serotonin (5-hydroxytryptamine; 5-HT) signaling, including depression and anxiety. During the first 2 weeks of postnatal life in rodents (equivalent to the third trimester of human pregnancy) 5-HT neurons undergo significant functional maturation and their axons reach target regions in the forebrain (e.g., cortex and hippocampus). The objective of this study was to identify the effects of third trimester ethanol (EtOH) exposure on hippocampal 5-HT signaling. Using EtOH vapor inhalation chambers, we exposed rat pups to EtOH for 4 h/day from postnatal day (P) 2 to P12. The average serum EtOH concentration in the pups was 0.13 ± 0.04 g/dl (legal intoxication limit in humans = 0.08 g/dl). We used brain slices to assess the modulatory actions of 5-HT on field excitatory postsynaptic potentials in the hippocampal CA3 region at P13-P15. Application of the GABAA/glycine receptor antagonist, picrotoxin, caused broadening of field excitatory postsynaptic potentials (fEPSPs), an effect that was reversed by application of 5-HT in slices from air exposed rats. However, this effect of 5-HT was absent in EtOH exposed animals. In slices from naïve animals, application of a 5-HT1A receptor antagonist blocked the effect of 5-HT on the fEPSPs recorded in presence of picrotoxin, suggesting that third trimester ethanol exposure acts by inhibiting the function of these receptors. Studies indicate that 5-HT1A receptors play a critical role in the development of hippocampal circuits. Therefore, inhibition of these receptors by third trimester ethanol exposure could contribute to the pathophysiology of fetal alcohol spectrum disorders. PMID:27375424

  7. Synaptic vesicle endocytosis.

    Science.gov (United States)

    Saheki, Yasunori; De Camilli, Pietro

    2012-09-01

    Neurons can sustain high rates of synaptic transmission without exhausting their supply of synaptic vesicles. This property relies on a highly efficient local endocytic recycling of synaptic vesicle membranes, which can be reused for hundreds, possibly thousands, of exo-endocytic cycles. Morphological, physiological, molecular, and genetic studies over the last four decades have provided insight into the membrane traffic reactions that govern this recycling and its regulation. These studies have shown that synaptic vesicle endocytosis capitalizes on fundamental and general endocytic mechanisms but also involves neuron-specific adaptations of such mechanisms. Thus, investigations of these processes have advanced not only the field of synaptic transmission but also, more generally, the field of endocytosis. This article summarizes current information on synaptic vesicle endocytosis with an emphasis on the underlying molecular mechanisms and with a special focus on clathrin-mediated endocytosis, the predominant pathway of synaptic vesicle protein internalization.

  8. Biphasic calcium phosphate in periapical surgery

    OpenAIRE

    Suneelkumar, Chinni; Datta, Krithika; Manali R Srinivasan; Kumar, Sampath T

    2008-01-01

    Calcium phosphate ceramics like hydroxyapatite and β -tricalcium phosphate (β -TCP) possess mineral composition that closely resembles that of the bone. They can be good bone substitutes due to their excellent biocompatibility. Biphasic calcium phosphate is a bone substitute which is a mixture of hydroxyapatite and β -tricalcium phosphate in fixed ratios. Studies have demonstrated the osteoconductive potential of this composition. This paper highlights the clinical use of biphasic calcium pho...

  9. Acute Biphasic Effects of Ayahuasca.

    Science.gov (United States)

    Schenberg, Eduardo Ekman; Alexandre, João Felipe Morel; Filev, Renato; Cravo, Andre Mascioli; Sato, João Ricardo; Muthukumaraswamy, Suresh D; Yonamine, Maurício; Waguespack, Marian; Lomnicka, Izabela; Barker, Steven A; da Silveira, Dartiu Xavier

    2015-01-01

    Ritual use of ayahuasca, an amazonian Amerindian medicine turned sacrament in syncretic religions in Brazil, is rapidly growing around the world. Because of this internationalization, a comprehensive understanding of the pharmacological mechanisms of action of the brew and the neural correlates of the modified states of consciousness it induces is important. Employing a combination of electroencephalogram (EEG) recordings and quantification of ayahuasca's compounds and their metabolites in the systemic circulation we found ayahuasca to induce a biphasic effect in the brain. This effect was composed of reduced power in the alpha band (8-13 Hz) after 50 minutes from ingestion of the brew and increased slow- and fast-gamma power (30-50 and 50-100 Hz, respectively) between 75 and 125 minutes. Alpha power reductions were mostly located at left parieto-occipital cortex, slow-gamma power increase was observed at left centro-parieto-occipital, left fronto-temporal and right frontal cortices while fast-gamma increases were significant at left centro-parieto-occipital, left fronto-temporal, right frontal and right parieto-occipital cortices. These effects were significantly associated with circulating levels of ayahuasca's chemical compounds, mostly N,N-dimethyltryptamine (DMT), harmine, harmaline and tetrahydroharmine and some of their metabolites. An interpretation based on a cognitive and emotional framework relevant to the ritual use of ayahuasca, as well as it's potential therapeutic effects is offered. PMID:26421727

  10. Acute Biphasic Effects of Ayahuasca.

    Directory of Open Access Journals (Sweden)

    Eduardo Ekman Schenberg

    Full Text Available Ritual use of ayahuasca, an amazonian Amerindian medicine turned sacrament in syncretic religions in Brazil, is rapidly growing around the world. Because of this internationalization, a comprehensive understanding of the pharmacological mechanisms of action of the brew and the neural correlates of the modified states of consciousness it induces is important. Employing a combination of electroencephalogram (EEG recordings and quantification of ayahuasca's compounds and their metabolites in the systemic circulation we found ayahuasca to induce a biphasic effect in the brain. This effect was composed of reduced power in the alpha band (8-13 Hz after 50 minutes from ingestion of the brew and increased slow- and fast-gamma power (30-50 and 50-100 Hz, respectively between 75 and 125 minutes. Alpha power reductions were mostly located at left parieto-occipital cortex, slow-gamma power increase was observed at left centro-parieto-occipital, left fronto-temporal and right frontal cortices while fast-gamma increases were significant at left centro-parieto-occipital, left fronto-temporal, right frontal and right parieto-occipital cortices. These effects were significantly associated with circulating levels of ayahuasca's chemical compounds, mostly N,N-dimethyltryptamine (DMT, harmine, harmaline and tetrahydroharmine and some of their metabolites. An interpretation based on a cognitive and emotional framework relevant to the ritual use of ayahuasca, as well as it's potential therapeutic effects is offered.

  11. Huperzine A enhances excitatory synaptic transmission in CA1 pyramidal neurons of adult rat hippocampal slices%石杉碱甲增强大鼠海马脑片CA1锥体神经元的兴奋性突触传递

    Institute of Scientific and Technical Information of China (English)

    吴小未; 王邦安; 汪萌芽

    2012-01-01

    AIM: To observe the effects of huperzine A (Hup-A) on excitatory synaptic transmission in CA1 pyramidal neurons of adult rat hippocampal slices and to gain an insight into the cellular electrophysiological mechanisms underlying the potentiation of learning and memory by Hup-A. METHODS: The intracellular recordings from CA1 pyramidal neurons in hippocampal slices related to learning and memory were made to analyze mechanisms of Hup-A actions on cell electrophysiological properties and excitatory postsynaptic potential (EPSP) evoked by stimulating Schaffer collaterals. RESULTS; (1) During bath of Hup-A (1 μmol/L), the changes of cell electrophysiological properties were not significant (P>0. 05). (2) Superfu-sion of Hup-A (0. 3 - 3. 0 μmol/L, 15 min) in- creased amplitude, duration and area under curve of EPSPs, which was concentration-dependent, recoverable, but sensitive to atropine pretreatment (10 μmol/L, n = 4). (3) Hup-A did not result in remarkable changes of depolarizing response induced by exogenous glutamate (n=5). CONCLUSION, By the facilitation of the synaptic transmissions, Hup-A may potentiate the activities of hippocampal CA1 pyramidal neurons, and its actions on EPSP is related to the excitation of muscarinic type of acetylcholin-ergic receptors.%目的:观察石杉碱甲(Hup-A)对海马CA1锥体神经元兴奋性突触传递的影响,以探讨其增强学习记忆功能的神经细胞电生理机制.方法:应用大鼠海马脑片CA1锥体神经元细胞内记录技术,观察Hup-A对大鼠海马CA1锥体神经元膜电性质和刺激Schaffer侧支诱发的兴奋性突触后电位( EPSP)的影响.结果:(1) Hup-A(1 μmol/L)灌流15 min对CA1锥体神经元的膜电性质没有显著性影响.(2) Hup-A (0.3~3.0 μmol/L)浓度依赖性使EPSP幅度升高、时程延长、曲线下面积增大,该作用可被阿托品(10μmol/L)预处理取消.(3)Hup-A对外源性谷氨酸诱导的去极化反应无明显影响.结论:Hup-A可增强CA1

  12. 消退训练对大鼠条件性恐惧行为及海马CA1区突触超微结构的影响%Effects of extinction training on conditioned fear behaviour and synaptic structure in hippocampal CA1 area in fear conditioned rats

    Institute of Scientific and Technical Information of China (English)

    张丽丽; 李培培; 李敏; 韦美; 彭李

    2012-01-01

    Objective To determine the effect of fear extinction training on the behaviours and the ultrastructure of hippocampal CA1 area in fear conditioned rats. Methods Forty male adult SD rats were randomly divided into native group (re =8), extinction control group (re = 16) and extinction group (re = 16). In 24 h after fear condition was established by reference instruction in the later 2 groups, extinction training was carried out in the extinction group and extinction retention test was performed in 7 and 21 d after fear extinction. The test was performed in 8 and 22 d in extinction control group. The changes of synaptic structure in CA1 of hippocampus were observed at 7 and 21 d after fear extinction. Results Compared with the extinction control group, the scores of extinction retention was significantly increased (P<0.01) at 7 and 21 d after extinction in the extinction group. There was no significant difference between extinction group and native group at 7 and 21 d. At 7 d after extinction training, the synaptic density was significantly higher in extinction group than that in the extinction control group (P <0.05 ) , and there was no difference among groups at 21 d. Compared with native group, the width of synaptic gap was significantly lower at 7 and 21 d after extinction training in extinction group ( P <0.01, 0. 05 ). At 21 d, the width of synaptic gap was significantly lower in the extinction group than that in the control group (P <0. 05). But there was no significant difference between the extinction control group and native group at 7 and 21 d after extinction. Compared with native group, at 7 and 21 d after extinction training, postsynaptic density (PSD) was significantly thicker in extinction group (P<0.01). And at 21 d, the density was significantly thicker in extinction group than that in the extinction control group (P < 0.05 ). There was no significant difference among the groups in active zone length. Conclusion Fear extinction training changes

  13. Synaptic Homeostasis and Restructuring across the Sleep-Wake Cycle.

    Science.gov (United States)

    Blanco, Wilfredo; Pereira, Catia M; Cota, Vinicius R; Souza, Annie C; Rennó-Costa, César; Santos, Sharlene; Dias, Gabriella; Guerreiro, Ana M G; Tort, Adriano B L; Neto, Adrião D; Ribeiro, Sidarta

    2015-05-01

    Sleep is critical for hippocampus-dependent memory consolidation. However, the underlying mechanisms of synaptic plasticity are poorly understood. The central controversy is on whether long-term potentiation (LTP) takes a role during sleep and which would be its specific effect on memory. To address this question, we used immunohistochemistry to measure phosphorylation of Ca2+/calmodulin-dependent protein kinase II (pCaMKIIα) in the rat hippocampus immediately after specific sleep-wake states were interrupted. Control animals not exposed to novel objects during waking (WK) showed stable pCaMKIIα levels across the sleep-wake cycle, but animals exposed to novel objects showed a decrease during subsequent slow-wave sleep (SWS) followed by a rebound during rapid-eye-movement sleep (REM). The levels of pCaMKIIα during REM were proportional to cortical spindles near SWS/REM transitions. Based on these results, we modeled sleep-dependent LTP on a network of fully connected excitatory neurons fed with spikes recorded from the rat hippocampus across WK, SWS and REM. Sleep without LTP orderly rescaled synaptic weights to a narrow range of intermediate values. In contrast, LTP triggered near the SWS/REM transition led to marked swaps in synaptic weight ranking. To better understand the interaction between rescaling and restructuring during sleep, we implemented synaptic homeostasis and embossing in a detailed hippocampal-cortical model with both excitatory and inhibitory neurons. Synaptic homeostasis was implemented by weakening potentiation and strengthening depression, while synaptic embossing was simulated by evoking LTP on selected synapses. We observed that synaptic homeostasis facilitates controlled synaptic restructuring. The results imply a mechanism for a cognitive synergy between SWS and REM, and suggest that LTP at the SWS/REM transition critically influences the effect of sleep: Its lack determines synaptic homeostasis, its presence causes synaptic

  14. Synaptic Homeostasis and Restructuring across the Sleep-Wake Cycle.

    Directory of Open Access Journals (Sweden)

    Wilfredo Blanco

    2015-05-01

    Full Text Available Sleep is critical for hippocampus-dependent memory consolidation. However, the underlying mechanisms of synaptic plasticity are poorly understood. The central controversy is on whether long-term potentiation (LTP takes a role during sleep and which would be its specific effect on memory. To address this question, we used immunohistochemistry to measure phosphorylation of Ca2+/calmodulin-dependent protein kinase II (pCaMKIIα in the rat hippocampus immediately after specific sleep-wake states were interrupted. Control animals not exposed to novel objects during waking (WK showed stable pCaMKIIα levels across the sleep-wake cycle, but animals exposed to novel objects showed a decrease during subsequent slow-wave sleep (SWS followed by a rebound during rapid-eye-movement sleep (REM. The levels of pCaMKIIα during REM were proportional to cortical spindles near SWS/REM transitions. Based on these results, we modeled sleep-dependent LTP on a network of fully connected excitatory neurons fed with spikes recorded from the rat hippocampus across WK, SWS and REM. Sleep without LTP orderly rescaled synaptic weights to a narrow range of intermediate values. In contrast, LTP triggered near the SWS/REM transition led to marked swaps in synaptic weight ranking. To better understand the interaction between rescaling and restructuring during sleep, we implemented synaptic homeostasis and embossing in a detailed hippocampal-cortical model with both excitatory and inhibitory neurons. Synaptic homeostasis was implemented by weakening potentiation and strengthening depression, while synaptic embossing was simulated by evoking LTP on selected synapses. We observed that synaptic homeostasis facilitates controlled synaptic restructuring. The results imply a mechanism for a cognitive synergy between SWS and REM, and suggest that LTP at the SWS/REM transition critically influences the effect of sleep: Its lack determines synaptic homeostasis, its presence causes

  15. Extracellular ATP hydrolysis inhibits synaptic transmission by increasing ph buffering in the synaptic cleft.

    Directory of Open Access Journals (Sweden)

    Rozan Vroman

    2014-05-01

    Full Text Available Neuronal computations strongly depend on inhibitory interactions. One such example occurs at the first retinal synapse, where horizontal cells inhibit photoreceptors. This interaction generates the center/surround organization of bipolar cell receptive fields and is crucial for contrast enhancement. Despite its essential role in vision, the underlying synaptic mechanism has puzzled the neuroscience community for decades. Two competing hypotheses are currently considered: an ephaptic and a proton-mediated mechanism. Here we show that horizontal cells feed back to photoreceptors via an unexpected synthesis of the two. The first one is a very fast ephaptic mechanism that has no synaptic delay, making it one of the fastest inhibitory synapses known. The second one is a relatively slow (τ≈200 ms, highly intriguing mechanism. It depends on ATP release via Pannexin 1 channels located on horizontal cell dendrites invaginating the cone synaptic terminal. The ecto-ATPase NTPDase1 hydrolyses extracellular ATP to AMP, phosphate groups, and protons. The phosphate groups and protons form a pH buffer with a pKa of 7.2, which keeps the pH in the synaptic cleft relatively acidic. This inhibits the cone Ca²⁺ channels and consequently reduces the glutamate release by the cones. When horizontal cells hyperpolarize, the pannexin 1 channels decrease their conductance, the ATP release decreases, and the formation of the pH buffer reduces. The resulting alkalization in the synaptic cleft consequently increases cone glutamate release. Surprisingly, the hydrolysis of ATP instead of ATP itself mediates the synaptic modulation. Our results not only solve longstanding issues regarding horizontal cell to photoreceptor feedback, they also demonstrate a new form of synaptic modulation. Because pannexin 1 channels and ecto-ATPases are strongly expressed in the nervous system and pannexin 1 function is implicated in synaptic plasticity, we anticipate that this novel form

  16. Effect of different Intensity Exercises in Treadmill on Learning and Memory and The Synaptic Ultrastructure in Hippocampal CA3 Area in Rats%不同强度跑台运动对大鼠学习记忆能力及海马CA3区突触超微结构的影响

    Institute of Scientific and Technical Information of China (English)

    龚云

    2012-01-01

    Effect of the different intensity treadmill exercise on learning and memory ability and hippocampal CA3 area ultrastructure was studied in rats.40 SD rats were randomly divided into four groups(control group,low-intensity exercise group,medium-intensity exercise group and high-intensity exercise group),after 60d exercise according to their respective intensity,through the one-trial passive avoidance response,the time to step-through lateney(STL) of rats was measured in every exercise group.Then 5 rats were chosen from every group,through normal ultrathin section made method,hippocampal CA3 area was observed under JEM-1230EX transmission electron microscope and photographed.The results showed that: 24 hours of STL period after electrical shock was significantly longer(P0.05) in low-intensity exercise group rats,and the hippocampal CA3 area postsynaptic density material became significantly thicker(P0.01).The curved type of synaptic interface could be divided into positively curved,negatively curved and flat,the flat type was the main.As a result,low-intensity exercise can increase memory capacity,and make the neuron synapse occurring plastic changes in the hippocampal CA3 area.The thickness of postsynaptic density material came into being a positive correlation with the strength of memory.%探讨不同强度跑台运动对大鼠学习记忆能力及海马CA3区超微结构的影响。40只Wister大鼠随机被分为4组(对照组、低强度运动组、中强度运动组、高强度运动组,各10只),按各自强度运动60 d后,通过一次性被动回避反应实验,逐只测量其步入潜伏期的时间(STL);后每组任选5只大鼠,取右侧海马CA3区按常规方法制作超薄切片,60K倍透射电镜观察并拍照,Motic Images Advanced 3.1软件测量相关突触界面结构。结果表明:低强度运动组大鼠,电击后24 h步入潜伏期的时间显著延长(P〈0.05),海马CA3区突触后膜致密

  17. Synaptic Plasticity and Nociception

    Institute of Scientific and Technical Information of China (English)

    ChenJianguo

    2004-01-01

    Synaptic plasticity is one of the fields that progresses rapidly and has a lot of success in neuroscience. The two major types of synaptie plasticity: long-term potentiation ( LTP and long-term depression (LTD are thought to be the cellular mochanisms of learning and memory. Recently, accumulating evidence suggests that, besides serving as a cellular model for learning and memory, the synaptic plasticity involves in other physiological or pathophysiological processes, such as the perception of pain and the regulation of cardiovascular system. This minireview will focus on the relationship between synaptic plasticity and nociception.

  18. Synaptic Vesicle Exocytosis

    OpenAIRE

    Südhof, Thomas C; Rizo, Josep

    2011-01-01

    Presynaptic nerve terminals release neurotransmitters by synaptic vesicle exocytosis. Membrane fusion mediating synaptic exocytosis and other intracellular membrane traffic is affected by a universal machinery that includes SNARE (for “soluble NSF-attachment protein receptor”) and SM (for “Sec1/Munc18-like”) proteins. During fusion, vesicular and target SNARE proteins assemble into an α-helical trans-SNARE complex that forces the two membranes tightly together, and SM proteins likely wrap aro...

  19. A Framework for the Modelling of Biphasic Reacting Systems

    DEFF Research Database (Denmark)

    Anantpinijwatna, Amata; Sin, Gürkan; O’Connell, John P.;

    2014-01-01

    Biphasic reacting systems have a broad application range from organic reactions in pharmaceutical and agro-bio industries to CO 2 capture. However, mathematical modelling of biphasic reacting systems is a formidable challenge due to many phenomena underlying the process such as chemical equilibrium......, biphasic equilibrium, reaction kinetics, and transport/mixing. In this study, a framework for modelling biphasic reacting systems is proposed to fa cilitate the model development in support of model-based process design-analysis. This framework is successfully applied to describe two biphasic reaction...

  20. The roles of STP and LTP in synaptic encoding

    Directory of Open Access Journals (Sweden)

    Arturas Volianskis

    2013-02-01

    Full Text Available Long-term potentiation (LTP, a cellular model of learning and memory, is generally regarded as a unitary phenomenon that alters the strength of synaptic transmission by increasing the postsynaptic response to the release of a quantum of neurotransmitter. LTP, at CA3-CA1 synapses in the hippocampus, contains a stimulation-labile phase of short-term potentiation (STP, or transient LTP, t-LTP that decays into stable LTP. By studying the responses of populations of neurons to brief bursts of high-frequency afferent stimulation before and after the induction of LTP, we found that synaptic responses during bursts are potentiated equally during LTP but not during STP. We show that STP modulates the frequency response of synaptic transmission whereas LTP preserves the fidelity. Thus, STP and LTP have different functional consequences for the transfer of synaptic information.

  1. Glucose rapidly induces different forms of excitatory synaptic plasticity in hypothalamic POMC neurons.

    Directory of Open Access Journals (Sweden)

    Jun Hu

    Full Text Available Hypothalamic POMC neurons are required for glucose and energy homeostasis. POMC neurons have a wide synaptic connection with neurons both within and outside the hypothalamus, and their activity is controlled by a balance between excitatory and inhibitory synaptic inputs. Brain glucose-sensing plays an essential role in the maintenance of normal body weight and metabolism; however, the effect of glucose on synaptic transmission in POMC neurons is largely unknown. Here we identified three types of POMC neurons (EPSC(+, EPSC(-, and EPSC(+/- based on their glucose-regulated spontaneous excitatory postsynaptic currents (sEPSCs, using whole-cell patch-clamp recordings. Lowering extracellular glucose decreased the frequency of sEPSCs in EPSC(+ neurons, but increased it in EPSC(- neurons. Unlike EPSC(+ and EPSC(- neurons, EPSC(+/- neurons displayed a bi-phasic sEPSC response to glucoprivation. In the first phase of glucoprivation, both the frequency and the amplitude of sEPSCs decreased, whereas in the second phase, they increased progressively to the levels above the baseline values. Accordingly, lowering glucose exerted a bi-phasic effect on spontaneous action potentials in EPSC(+/- neurons. Glucoprivation decreased firing rates in the first phase, but increased them in the second phase. These data indicate that glucose induces distinct excitatory synaptic plasticity in different subpopulations of POMC neurons. This synaptic remodeling is likely to regulate the sensitivity of the melanocortin system to neuronal and hormonal signals.

  2. Achieving High-Frequency Optical Control of Synaptic Transmission

    Science.gov (United States)

    Jackman, Skyler L.; Beneduce, Brandon M.; Drew, Iain R.

    2014-01-01

    The optogenetic tool channelrhodopsin-2 (ChR2) is widely used to excite neurons to study neural circuits. Previous optogenetic studies of synapses suggest that light-evoked synaptic responses often exhibit artificial synaptic depression, which has been attributed to either the inability of ChR2 to reliably fire presynaptic axons or to ChR2 elevating the probability of release by depolarizing presynaptic boutons. Here, we compare light-evoked and electrically evoked synaptic responses for high-frequency stimulation at three synapses in the mouse brain. At synapses from Purkinje cells to deep cerebellar nuclei neurons (PC→DCN), light- and electrically evoked synaptic currents were remarkably similar for ChR2 expressed transgenically or with adeno-associated virus (AAV) expression vectors. For hippocampal CA3→CA1 synapses, AAV expression vectors of serotype 1, 5, and 8 led to light-evoked synaptic currents that depressed much more than electrically evoked currents, even though ChR2 could fire axons reliably at up to 50 Hz. The disparity between optical and electrical stimulation was eliminated when ChR2 was expressed transgenically or with AAV9. For cerebellar granule cell to stellate cell (grc→SC) synapses, AAV1 also led to artificial synaptic depression and AAV9 provided superior performance. Artificial synaptic depression also occurred when stimulating over presynaptic boutons, rather than axons, at CA3→CA1 synapses, but not at PC→DCN synapses. These findings indicate that ChR2 expression methods and light stimulation techniques influence synaptic responses in a neuron-specific manner. They also identify pitfalls associated with using ChR2 to study synapses and suggest an approach that allows optogenetics to be applied in a manner that helps to avoid potential complications. PMID:24872574

  3. Pannexin 1 Regulates Bidirectional Hippocampal Synaptic Plasticity in Adult Mice

    Directory of Open Access Journals (Sweden)

    Alvaro O. Ardiles

    2014-10-01

    Full Text Available The threshold for bidirectional modification of synaptic plasticity is known to be controlled by several factors, including the balance between protein phosphorylation and dephosphorylation, postsynaptic free Ca2+ concentration and NMDA receptor (NMDAR composition of GluN2 subunits. Pannexin 1 (Panx1, a member of the integral membrane protein family, has been shown to form non-selective channels and to regulate the induction of synaptic plasticity as well as hippocampal-dependent learning. Although Panx1 channels have been suggested to play a role in excitatory long-term potentiation (LTP, it remains unknown whether these channels also modulate long-term depression (LTD or the balance between both types of synaptic plasticity. To study how Panx1 contributes to excitatory synaptic efficacy, we examined the age-dependent effects of eliminating or blocking Panx1 channels on excitatory synaptic plasticity within the CA1 region of the mouse hippocampus. By using different protocols to induce bidirectional synaptic plasticity, Panx1 channel blockade or lack of Panx1 were found to enhance LTP, whereas both conditions precluded the induction of LTD in adults, but not in young animals. These findings suggest that Panx1 channels restrain the sliding threshold for the induction of synaptic plasticity and underlying brain mechanisms of learning and memory.

  4. Pannexin 1 regulates bidirectional hippocampal synaptic plasticity in adult mice

    Science.gov (United States)

    Ardiles, Alvaro O.; Flores-Muñoz, Carolina; Toro-Ayala, Gabriela; Cárdenas, Ana M.; Palacios, Adrian G.; Muñoz, Pablo; Fuenzalida, Marco; Sáez, Juan C.; Martínez, Agustín D.

    2014-01-01

    The threshold for bidirectional modification of synaptic plasticity is known to be controlled by several factors, including the balance between protein phosphorylation and dephosphorylation, postsynaptic free Ca2+ concentration and NMDA receptor (NMDAR) composition of GluN2 subunits. Pannexin 1 (Panx1), a member of the integral membrane protein family, has been shown to form non-selective channels and to regulate the induction of synaptic plasticity as well as hippocampal-dependent learning. Although Panx1 channels have been suggested to play a role in excitatory long-term potentiation (LTP), it remains unknown whether these channels also modulate long-term depression (LTD) or the balance between both types of synaptic plasticity. To study how Panx1 contributes to excitatory synaptic efficacy, we examined the age-dependent effects of eliminating or blocking Panx1 channels on excitatory synaptic plasticity within the CA1 region of the mouse hippocampus. By using different protocols to induce bidirectional synaptic plasticity, Panx1 channel blockade or lack of Panx1 were found to enhance LTP, whereas both conditions precluded the induction of LTD in adults, but not in young animals. These findings suggest that Panx1 channels restrain the sliding threshold for the induction of synaptic plasticity and underlying brain mechanisms of learning and memory. PMID:25360084

  5. Metal separations using aqueous biphasic partitioning systems

    Energy Technology Data Exchange (ETDEWEB)

    Chaiko, D.J.; Zaslavsky, B.; Rollins, A.N.; Vojta, Y.; Gartelmann, J.; Mego, W. [Argonne National Lab., IL (United States). Chemical Technology Div.

    1996-05-01

    Aqueous biphasic extraction (ABE) processes offer the potential for low-cost, highly selective separations. This countercurrent extraction technique involves selective partitioning of either dissolved solutes or ultrafine particulates between two immiscible aqueous phases. The extraction systems that the authors have studied are generated by combining an aqueous salt solution with an aqueous polymer solution. They have examined a wide range of applications for ABE, including the treatment of solid and liquid nuclear wastes, decontamination of soils, and processing of mineral ores. They have also conducted fundamental studies of solution microstructure using small angle neutron scattering (SANS). In this report they review the physicochemical fundamentals of aqueous biphase formation and discuss the development and scaleup of ABE processes for environmental remediation.

  6. [Peptidergic modulation of the hippocampus synaptic activity].

    Science.gov (United States)

    Skrebitskiĭ, V G; Kondratenko, R V; Povarov, I S; Dereviagin, V I

    2011-11-01

    Effects of two newly synthesized nootropic and anxiolytic dipeptides: Noopept and Selank on inhibitory synaptic transmission in hippocampal CA1 pyramidal cells were investigated using patch-clamp technique in whole-cell configuration. Bath application of Noopept (1 microM) or Selank (2 microM) significantly increased the frequency of spike-dependent spontaneous m1PSCs, whereas spike-independent mlPSCs remained unchanged. It was suggested that both peptides mediated their effect sue to activation of inhibitory interneurons terminating on CA1 pyramidal cells. Results of current clamp recording of inhibitory interneurons residing in stratum radiatum confirmed this suggestion, at least for Noonent. PMID:22390072

  7. Brief dendritic calcium signals initiate long-lasting synaptic depression in cerebellar Purkinje cells.

    OpenAIRE

    Konnerth, A.; Dreessen, J; Augustine, G J

    1992-01-01

    We have performed experiments designed to test the hypothesis that long-term depression (LTD) of excitatory synaptic transmission in the cerebellar cortex is caused by a rise in postsynaptic Ca concentration. These experiments combined measurements of synaptic efficacy, performed with the thin slice patch clamp technique, with fura-2 measurements of intracellular Ca concentration ([Ca]i) in single cerebellar Purkinje cells. Simultaneous activation of the climbing fiber and parallel fibers inn...

  8. Lavandula angustifolia extract improves deteriorated synaptic plasticity in an animal model of Alzheimer’s disease

    OpenAIRE

    Masoud Soheili; Mostafa Rezaei Tavirany; Mahmoud Salami

    2015-01-01

    Objective(s): Neurodegenerative Alzheimer’s disease (AD) is associated with profound deficits in synaptic transmission and synaptic plasticity. Long-term potentiation (LTP), an experimental form of synaptic plasticity, is intensively examined in hippocampus. In this study we evaluated the effect of aqueous extract of lavender (Lavandula angustifolia) on induction of LTP in the CA1 area of hippocampus. In response to stimulation of the Schaffer collaterals the baseline or tetanized field extra...

  9. Synapse geometry and receptor dynamics modulate synaptic strength.

    Directory of Open Access Journals (Sweden)

    Dominik Freche

    Full Text Available Synaptic transmission relies on several processes, such as the location of a released vesicle, the number and type of receptors, trafficking between the postsynaptic density (PSD and extrasynaptic compartment, as well as the synapse organization. To study the impact of these parameters on excitatory synaptic transmission, we present a computational model for the fast AMPA-receptor mediated synaptic current. We show that in addition to the vesicular release probability, due to variations in their release locations and the AMPAR distribution, the postsynaptic current amplitude has a large variance, making a synapse an intrinsic unreliable device. We use our model to examine our experimental data recorded from CA1 mice hippocampal slices to study the differences between mEPSC and evoked EPSC variance. The synaptic current but not the coefficient of variation is maximal when the active zone where vesicles are released is apposed to the PSD. Moreover, we find that for certain type of synapses, receptor trafficking can affect the magnitude of synaptic depression. Finally, we demonstrate that perisynaptic microdomains located outside the PSD impacts synaptic transmission by regulating the number of desensitized receptors and their trafficking to the PSD. We conclude that geometrical modifications, reorganization of the PSD or perisynaptic microdomains modulate synaptic strength, as the mechanisms underlying long-term plasticity.

  10. Bilinearity in spatiotemporal integration of synaptic inputs.

    Directory of Open Access Journals (Sweden)

    Songting Li

    2014-12-01

    Full Text Available Neurons process information via integration of synaptic inputs from dendrites. Many experimental results demonstrate dendritic integration could be highly nonlinear, yet few theoretical analyses have been performed to obtain a precise quantitative characterization analytically. Based on asymptotic analysis of a two-compartment passive cable model, given a pair of time-dependent synaptic conductance inputs, we derive a bilinear spatiotemporal dendritic integration rule. The summed somatic potential can be well approximated by the linear summation of the two postsynaptic potentials elicited separately, plus a third additional bilinear term proportional to their product with a proportionality coefficient [Formula: see text]. The rule is valid for a pair of synaptic inputs of all types, including excitation-inhibition, excitation-excitation, and inhibition-inhibition. In addition, the rule is valid during the whole dendritic integration process for a pair of synaptic inputs with arbitrary input time differences and input locations. The coefficient [Formula: see text] is demonstrated to be nearly independent of the input strengths but is dependent on input times and input locations. This rule is then verified through simulation of a realistic pyramidal neuron model and in electrophysiological experiments of rat hippocampal CA1 neurons. The rule is further generalized to describe the spatiotemporal dendritic integration of multiple excitatory and inhibitory synaptic inputs. The integration of multiple inputs can be decomposed into the sum of all possible pairwise integration, where each paired integration obeys the bilinear rule. This decomposition leads to a graph representation of dendritic integration, which can be viewed as functionally sparse.

  11. Astrocytes mediate in vivo cholinergic-induced synaptic plasticity.

    Directory of Open Access Journals (Sweden)

    Marta Navarrete

    2012-02-01

    Full Text Available Long-term potentiation (LTP of synaptic transmission represents the cellular basis of learning and memory. Astrocytes have been shown to regulate synaptic transmission and plasticity. However, their involvement in specific physiological processes that induce LTP in vivo remains unknown. Here we show that in vivo cholinergic activity evoked by sensory stimulation or electrical stimulation of the septal nucleus increases Ca²⁺ in hippocampal astrocytes and induces LTP of CA3-CA1 synapses, which requires cholinergic muscarinic (mAChR and metabotropic glutamate receptor (mGluR activation. Stimulation of cholinergic pathways in hippocampal slices evokes astrocyte Ca²⁺ elevations, postsynaptic depolarizations of CA1 pyramidal neurons, and LTP of transmitter release at single CA3-CA1 synapses. Like in vivo, these effects are mediated by mAChRs, and this cholinergic-induced LTP (c-LTP also involves mGluR activation. Astrocyte Ca²⁺ elevations and LTP are absent in IP₃R2 knock-out mice. Downregulating astrocyte Ca²⁺ signal by loading astrocytes with BAPTA or GDPβS also prevents LTP, which is restored by simultaneous astrocyte Ca²⁺ uncaging and postsynaptic depolarization. Therefore, cholinergic-induced LTP requires astrocyte Ca²⁺ elevations, which stimulate astrocyte glutamate release that activates mGluRs. The cholinergic-induced LTP results from the temporal coincidence of the postsynaptic activity and the astrocyte Ca²⁺ signal simultaneously evoked by cholinergic activity. Therefore, the astrocyte Ca²⁺ signal is necessary for cholinergic-induced synaptic plasticity, indicating that astrocytes are directly involved in brain storage information.

  12. Biphasic mini-reactor for characterization of biocatalyst performance

    OpenAIRE

    Van Den Wittenboer, Anne; Schmidt, Thomas; Müller, Pia; Ansorge-Schumacher, Marion Bettina; Greiner, Lasse

    2009-01-01

    Abstract Biphasic reaction media are extending the scope of technical biocatalysis. Thorough investigation of the factors affecting catalyst performance under these conditions is of key importance for the successful implementation of catalytic processes. Here, we present a reactor setup suitable for comprehensive systematic characterization and optimization of biocatalyzed reactions in biphasic systems with distinct phases. It is distinguished by small volumes allowing reproducible...

  13. Optogenetics and synaptic plasticity.

    Science.gov (United States)

    Xie, Yu-feng; Jackson, Michael F; Macdonald, John F

    2013-11-01

    The intricate and complex interaction between different populations of neurons in the brain has imposed limits on our ability to gain detailed understanding of synaptic transmission and its integration when employing classical electrophysiological approaches. Indeed, electrical field stimulation delivered via traditional microelectrodes does not permit the targeted, precise and selective control of neuronal activity amongst a varied population of neurons and their inputs (eg, cholinergic, dopaminergic or glutamatergic neurons). Recently established optogenetic techniques overcome these limitations allowing precise control of the target neuron populations, which is essential for the elucidation of the neural substrates underlying complex animal behaviors. Indeed, by introducing light-activated channels (ie, microbial opsin genes) into specific neuronal populations, optogenetics enables non-invasive optical control of specific neurons with milliseconds precision. These approaches can readily be applied to freely behaving live animals. Recently there is increased interests in utilizing optogenetics tools to understand synaptic plasticity and learning/memory. Here, we summarize recent progress in applying optogenetics in in the study of synaptic plasticity.

  14. AQUEOUS BIPHASE EXTRACTION FOR PROCESSING OF FINE COAL

    Energy Technology Data Exchange (ETDEWEB)

    K. Osseo-Asare; X. Zeng

    2002-01-01

    The objective of this research project is to develop an aqueous biphase extraction process for the treatment of fine coals. Aqueous biphase extraction is an advanced separation technology that relies on the ability of an aqueous system consisting of a water-soluble polymer and another component, e.g., another polymer, an inorganic salt, or a nonionic surfactant, to separate into two immiscible aqueous phases. The principle behind the partition of solid particles in aqueous biphase systems is the physicochemical interaction between the solid surface and the surrounding liquid solution. In order to remove sulfur and mineral matter from fine coal with aqueous biphasic extraction, it is necessary to know the partitioning behavior of coal, as well as the inorganic mineral components. Therefore, in this research emphasis was placed on the partitioning behavior of fine coal particles as well as model fine inorganic particles in aqueous biphase systems.

  15. Kidins220/ARMS is a novel modulator of short-term synaptic plasticity in hippocampal GABAergic neurons.

    Directory of Open Access Journals (Sweden)

    Joachim Scholz-Starke

    Full Text Available Kidins220 (Kinase D interacting substrate of 220 kDa/ARMS (Ankyrin Repeat-rich Membrane Spanning is a scaffold protein highly expressed in the nervous system. Previous work on neurons with altered Kidins220/ARMS expression suggested that this protein plays multiple roles in synaptic function. In this study, we analyzed the effects of Kidins220/ARMS ablation on basal synaptic transmission and on a variety of short-term plasticity paradigms in both excitatory and inhibitory synapses using a recently described Kidins220 full knockout mouse. Hippocampal neuronal cultures prepared from embryonic Kidins220(-/- (KO and wild type (WT littermates were used for whole-cell patch-clamp recordings of spontaneous and evoked synaptic activity. Whereas glutamatergic AMPA receptor-mediated responses were not significantly affected in KO neurons, specific differences were detected in evoked GABAergic transmission. The recovery from synaptic depression of inhibitory post-synaptic currents in WT cells showed biphasic kinetics, both in response to paired-pulse and long-lasting train stimulation, while in KO cells the respective slow components were strongly reduced. We demonstrate that the slow recovery from synaptic depression in WT cells is caused by a transient reduction of the vesicle release probability, which is absent in KO neurons. These results suggest that Kidins220/ARMS is not essential for basal synaptic transmission and various forms of short-term plasticity, but instead plays a novel role in the mechanisms regulating the recovery of synaptic strength in GABAergic synapses.

  16. Synaptic Homeostasis and Restructuring across the Sleep-Wake Cycle

    OpenAIRE

    Wilfredo Blanco; Catia M Pereira; Vinicius R Cota; Annie C Souza; César Rennó-Costa; Sharlene Santos; Gabriella Dias; Guerreiro, Ana M. G.; Tort, Adriano B. L.; Adrião D Neto; Sidarta Ribeiro

    2015-01-01

    Sleep is critical for hippocampus-dependent memory consolidation. However, the underlying mechanisms of synaptic plasticity are poorly understood. The central controversy is on whether long-term potentiation (LTP) takes a role during sleep and which would be its specific effect on memory. To address this question, we used immunohistochemistry to measure phosphorylation of Ca2+/calmodulin-dependent protein kinase II (pCaMKIIα) in the rat hippocampus immediately after specific sleep-wake states...

  17. Obtaining of ceramics biphasic dense and porous

    International Nuclear Information System (INIS)

    Among the bioceramic hydroxyapatite (HAP) and beta-tricalcium phosphate (beta-TCP) are materials commonly used in biomedical field. Their combined properties result in a material with absorbable and at the same time with bioactive surface. Called biphasic ceramics such materials respond more quickly when exposed to physiological environment. In this work, powders of HAP/beta-TCP were obtained by chemical precipitation. After obtaining the post-phase was added at a ratio of 0, 15% and 30w% aqueous solutions of corn starch in order to obtain porous bodies. After mixing the resulting solutions were dried, resigned in tablet form and sintered at 1300 deg C. The initial powder was characterized by X-ray diffraction with Rietveld refinement to quantify the phases present. Bodies-of-evidence has been characterized by calculating the bulk density, X-ray diffraction (XRD), scanning electron microscopy and diametral compression. (author)

  18. Synaptic Gain-of-Function Effects of Mutant Cav2.1 Channels in a Mouse Model of Familial Hemiplegic Migraine Are Due to Increased Basal [Ca2+]i

    OpenAIRE

    Di Guilmi, Mariano N.; Wang, Tiantian; Inchauspe, Carlota Gonzalez; Forsythe, Ian D; Ferrari, Michel D; van den Maagdenberg, Arn M. J. M.; Borst, J. Gerard G.; Uchitel, Osvaldo D.

    2014-01-01

    Specific missense mutations in the CACNA1A gene, which encodes a subunit of voltage-gated CaV2.1 channels, are associated with familial hemiplegic migraine type 1 (FHM1), a rare monogenic subtype of common migraine with aura. We used transgenic knock-in (KI) mice harboring the human pathogenic FHM1 mutation S218L to study presynaptic Ca2+ currents, EPSCs, and in vivo activity at the calyx of Held synapse. Whole-cell patch-clamp recordings of presynaptic terminals from S218L KI mice showed a s...

  19. Synaptic gain-of-function effects of mutant Cav2.1 channels in a mouse model of familial hemiplegic migraine are due to increased basal [Ca2+]i

    NARCIS (Netherlands)

    M.N. Di Guilmi (Mariano); T. Wang (Teng); C.G. Inchauspe (Carlota Gonzalez); I.D. Forsythe (Ian); M.D. Ferrari (Michel); A.M.J.M. van der Maagdenberg (Arn M. J.); J.G.G. Borst (Gerard); O.D. Uchitel (Osvaldo)

    2014-01-01

    textabstractSpecific missense mutations in the CACNA1A gene, which encodes a subunit of voltage-gated CaV2.1 channels, are associated with familial hemiplegic migraine type 1 (FHM1), a rare monogenic subtype of common migraine with aura. We used transgenic knock-in (KI) mice harboring the human path

  20. Archaerhodopsin Selectively and Reversibly Silences Synaptic Transmission through Altered pH.

    Science.gov (United States)

    El-Gaby, Mohamady; Zhang, Yu; Wolf, Konstantin; Schwiening, Christof J; Paulsen, Ole; Shipton, Olivia A

    2016-08-23

    Tools that allow acute and selective silencing of synaptic transmission in vivo would be invaluable for understanding the synaptic basis of specific behaviors. Here, we show that presynaptic expression of the proton pump archaerhodopsin enables robust, selective, and reversible optogenetic synaptic silencing with rapid onset and offset. Two-photon fluorescence imaging revealed that this effect is accompanied by a transient increase in pH restricted to archaerhodopsin-expressing boutons. Crucially, clamping intracellular pH abolished synaptic silencing without affecting the archaerhodopsin-mediated hyperpolarizing current, indicating that changes in pH mediate the synaptic silencing effect. To verify the utility of this technique, we used trial-limited, archaerhodopsin-mediated silencing to uncover a requirement for CA3-CA1 synapses whose afferents originate from the left CA3, but not those from the right CA3, for performance on a long-term memory task. These results highlight optogenetic, pH-mediated silencing of synaptic transmission as a spatiotemporally selective approach to dissecting synaptic function in behaving animals. PMID:27524609

  1. Archaerhodopsin Selectively and Reversibly Silences Synaptic Transmission through Altered pH

    Directory of Open Access Journals (Sweden)

    Mohamady El-Gaby

    2016-08-01

    Full Text Available Tools that allow acute and selective silencing of synaptic transmission in vivo would be invaluable for understanding the synaptic basis of specific behaviors. Here, we show that presynaptic expression of the proton pump archaerhodopsin enables robust, selective, and reversible optogenetic synaptic silencing with rapid onset and offset. Two-photon fluorescence imaging revealed that this effect is accompanied by a transient increase in pH restricted to archaerhodopsin-expressing boutons. Crucially, clamping intracellular pH abolished synaptic silencing without affecting the archaerhodopsin-mediated hyperpolarizing current, indicating that changes in pH mediate the synaptic silencing effect. To verify the utility of this technique, we used trial-limited, archaerhodopsin-mediated silencing to uncover a requirement for CA3-CA1 synapses whose afferents originate from the left CA3, but not those from the right CA3, for performance on a long-term memory task. These results highlight optogenetic, pH-mediated silencing of synaptic transmission as a spatiotemporally selective approach to dissecting synaptic function in behaving animals.

  2. Synaptic encoding of temporal contiguity

    Directory of Open Access Journals (Sweden)

    Srdjan eOstojic

    2013-04-01

    Full Text Available Often we need to perform tasks in an environment that changes stochastically. In these situations it is important to learn the statistics of sequences of events in order to predict the future and the outcome of our actions. The statistical description of many of these sequences can be reduced to the set of probabilities that a particular event follows another event (temporal contiguity. Under these conditions, it is important to encode and store in our memory these transition probabilities. Here we show that for a large class of synaptic plasticity models, the distribution of synaptic strengths encodes transitions probabilities. Specifically, when the synaptic dynamics depend on pairs of contiguous events and the synapses can remember multiple instances of the transitions, then the average synaptic weights are a monotonic function of the transition probabilities. The synaptic weights converge to the distribution encoding the probabilities also when the correlations between consecutive synaptic modifications are considered. We studied how this distribution depends on the number of synaptic states for a specific model of a multi-state synapse with hard bounds. In the case of bistable synapses, the average synaptic weights are a smooth function of the transition probabilities and the accuracy of the encoding depends on the learning rate. As the number of synaptic states increases, the average synaptic weights become a step function of the transition probabilities. We finally show that the information stored in the synaptic weights can be read out by a simple rate-based neural network. Our study shows that synapses encode transition probabilities under general assumptions and this indicates that temporal contiguity is likely to be encoded and harnessed in almost every neural circuit in the brain.

  3. Synaptic electronics: materials, devices and applications.

    Science.gov (United States)

    Kuzum, Duygu; Yu, Shimeng; Wong, H-S Philip

    2013-09-27

    In this paper, the recent progress of synaptic electronics is reviewed. The basics of biological synaptic plasticity and learning are described. The material properties and electrical switching characteristics of a variety of synaptic devices are discussed, with a focus on the use of synaptic devices for neuromorphic or brain-inspired computing. Performance metrics desirable for large-scale implementations of synaptic devices are illustrated. A review of recent work on targeted computing applications with synaptic devices is presented.

  4. Synaptic electronics: materials, devices and applications

    International Nuclear Information System (INIS)

    In this paper, the recent progress of synaptic electronics is reviewed. The basics of biological synaptic plasticity and learning are described. The material properties and electrical switching characteristics of a variety of synaptic devices are discussed, with a focus on the use of synaptic devices for neuromorphic or brain-inspired computing. Performance metrics desirable for large-scale implementations of synaptic devices are illustrated. A review of recent work on targeted computing applications with synaptic devices is presented. (topical review)

  5. 大鼠海马星形胶质细胞对突触可塑性的影响%The relation between structurely synaptic plasticity and astroglia in the CA1 region of rat hippocampus

    Institute of Scientific and Technical Information of China (English)

    谭来勋; 孙圣刚; 段申汉; 王细林; 吴秀枝

    2005-01-01

    目的研究星形胶质细胞在神经系统发育成熟过程中对突触可塑性的调控规律.方法取健康初生、幼年和成年大鼠各10只,每只取脑切片,用免疫组织化学方法观察其海马CA1区的S100、胶质纤维酸性蛋白(GFAP)和P38免疫反应产物强度;HE染色法显示神经元胞体.结果初生大鼠海马CA1区中神经元大量存在,但S100、GFAP和P38表达均少,幼鼠的表达增加,但仍显著少于成鼠的表达(P<0.01).结论大鼠海马CA1区星形胶质细胞增殖与突触出现时间、突触数目增加及功能成熟有关.

  6. The Relative Contribution of NMDARs to Excitatory Postsynaptic Currents is Controlled by Ca2+-Induced Inactivation

    OpenAIRE

    Valiullina, Fliza; Zakharova, Yulia; Mukhtarov, Marat; Draguhn, Andreas; Burnashev, Nail; Rozov, Andrei

    2016-01-01

    NMDA receptors (NMDARs) are important mediators of excitatory synaptic transmission and plasticity. A hallmark of these channels is their high permeability to Ca2+. At the same time, they are themselves inhibited by the elevation of intracellular Ca2+ concentration. It is unclear however, whether the Ca2+ entry associated with single NMDAR mediated synaptic events is sufficient to self-inhibit their activation. Such auto-regulation would have important effects on the dynamics of synaptic exci...

  7. The relative contribution of NMDARs to excitatory postsynaptic currents is controlled by Ca2+-induced inactivation.

    OpenAIRE

    Fliza eValiullina; Yulia eZakharova; Andreas eDraguhn; Marat eMukhtarov; Nail eBurnashev; Andrei eRozov

    2016-01-01

    NMDA receptors (NMDARs) are important mediators of excitatory synaptic transmission and plasticity. A hallmark of these channels is their high permeability to Ca2+. At the same time, they are themselves inhibited by the elevation of intracellular Ca2+ concentration. It is unclear however, whether the Ca2+ entry associated with single NMDAR mediated synaptic events is sufficient to self-inhibit their activation. Such auto-regulation would have important effects on the dynamics of synaptic exci...

  8. Molecular Recognition within Synaptic Scaffolds

    DEFF Research Database (Denmark)

    Erlendsson, Simon

    domains, responsible for tethering their respective synaptic protein ligands. Therefore, understanding the specificity and binding mechanisms of PDZ domain proteins is essential to understand regulation of synaptic plasticity. PICK1 is a PDZ domain-containing scaffolding protein predominantly expressed...... and characterized in the postsynaptic neurons, where it is involved in regulating processes underlying LTP and LTD. However, PICK1 has also been found to interact with a wide range of other regulatory proteins, receptors and transporters, which implicates PICK1 in several processes important for proper synaptic...

  9. Prolonged adenosine A1 receptor activation in hypoxia and pial vessel disruption focal cortical ischemia facilitates clathrin-mediated AMPA receptor endocytosis and long-lasting synaptic inhibition in rat hippocampal CA3-CA1 synapses: differential regulation of GluA2 and GluA1 subunits by p38 MAPK and JNK.

    Science.gov (United States)

    Chen, Zhicheng; Xiong, Cherry; Pancyr, Cassandra; Stockwell, Jocelyn; Walz, Wolfgang; Cayabyab, Francisco S

    2014-07-16

    Activation of presynaptic adenosine A1 receptors (A1Rs) causes substantial synaptic depression during hypoxia/cerebral ischemia, but postsynaptic actions of A1Rs are less clear. We found that A1Rs and GluA2-containing AMPA receptors (AMPARs) form stable protein complexes from hippocampal brain homogenates and cultured hippocampal neurons from Sprague Dawley rats. In contrast, adenosine A2A receptors (A2ARs) did not coprecipitate or colocalize with GluA2-containing AMPARs. Prolonged stimulation of A1Rs with the agonist N(6)-cyclopentyladenosine (CPA) caused adenosine-induced persistent synaptic depression (APSD) in hippocampal brain slices, and APSD levels were blunted by inhibiting clathrin-mediated endocytosis of GluA2 subunits with the Tat-GluA2-3Y peptide. Using biotinylation and membrane fractionation assays, prolonged CPA incubation showed significant depletion of GluA2/GluA1 surface expression from hippocampal brain slices and cultured neurons. Tat-GluA2-3Y peptide or dynamin inhibitor Dynasore prevented CPA-induced GluA2/GluA1 internalization. Confocal imaging analysis confirmed that functional A1Rs, but not A2ARs, are required for clathrin-mediated AMPAR endocytosis in hippocampal neurons. Pharmacological inhibitors or shRNA knockdown of p38 MAPK and JNK prevented A1R-mediated internalization of GluA2 but not GluA1 subunits. Tat-GluA2-3Y peptide or A1R antagonist 8-cyclopentyl-1,3-dipropylxanthine also prevented hypoxia-mediated GluA2/GluA1 internalization. Finally, in a pial vessel disruption cortical stroke model, a unilateral cortical lesion compared with sham surgery reduced hippocampal GluA2, GluA1, and A1R surface expression and also caused synaptic depression in hippocampal slices that was consistent with AMPAR downregulation and decreased probability of transmitter release. Together, these results indicate a previously unknown mechanism for A1R-induced persistent synaptic depression involving clathrin-mediated GluA2 and GluA1 internalization that

  10. High-frequency stimulation-induced synaptic potentiation in dorsal and ventral CA1 hippocampal synapses: the involvement of NMDA receptors, mGluR5, and (L-type) voltage-gated calcium channels.

    Science.gov (United States)

    Papatheodoropoulos, Costas; Kouvaros, Stylianos

    2016-09-01

    The ability of the ventral hippocampus (VH) for long-lasting long-term potentiation (LTP) and the mechanisms underlying its lower ability for short-lasting LTP compared with the dorsal hippocampus (DH) are unknown. Using recordings of field excitatory postsynaptic potentials (EPSPs) from the CA1 field of adult rat hippocampal slices, we found that 200-Hz stimulation induced nondecremental LTP that was maintained for at least 7 h and was greater in the DH than in the VH. The interaction of NMDA receptors with L-type voltage-dependent calcium channels appeared to be more effective in the DH than in the VH. Furthermore, the LTP was significantly enhanced in the DH only, between 2 and 5 h post-tetanus. Furthermore, the mGluR5 contributed to the post-tetanic potentiation more in the VH than in the DH. PMID:27531836

  11. Synaptic control of motoneuronal excitability

    DEFF Research Database (Denmark)

    Rekling, J C; Funk, G D; Bayliss, D A;

    2000-01-01

    important in understanding the transformation of neural activity to motor behavior. Here, we review recent studies on the control of motoneuronal excitability, focusing on synaptic and cellular properties. We first present a background description of motoneurons: their development, anatomical organization......, and membrane properties, both passive and active. We then describe the general anatomical organization of synaptic input to motoneurons, followed by a description of the major transmitter systems that affect motoneuronal excitability, including ligands, receptor distribution, pre- and postsynaptic actions...

  12. Biphasic catalysis in water/carbon dioxide micellar systems

    Science.gov (United States)

    Jacobson, Gunilla B.; Tumas, William; Johnston, Keith P.

    2002-01-01

    A process is provided for catalyzing an organic reaction to form a reaction product by placing reactants and a catalyst for the organic reaction, the catalyst of a metal complex and at least one ligand soluble within one of the phases of said aqueous biphasic system, within an aqueous biphasic system including a water phase, a dense phase fluid, and a surfactant adapted for forming an emulsion or microemulsion within the aqueous biphasic system, the reactants soluble within one of the phases of the aqueous biphasic system and convertible in the presence of the catalyst to a product having low solubility in the phase in which the catalyst is soluble; and, maintaining the aqueous biphasic system under pressures, at temperatures, and for a period of time sufficient for the organic reaction to occur and form the reaction product and to maintain sufficient density on the dense phase fluid, the reaction product characterized as having low solubility in the phase in which the catalyst is soluble.

  13. Dopamine Regulates Aversive Contextual Learning and Associated In Vivo Synaptic Plasticity in the Hippocampus.

    Science.gov (United States)

    Broussard, John I; Yang, Kechun; Levine, Amber T; Tsetsenis, Theodoros; Jenson, Daniel; Cao, Fei; Garcia, Isabella; Arenkiel, Benjamin R; Zhou, Fu-Ming; De Biasi, Mariella; Dani, John A

    2016-03-01

    Dopamine release during reward-driven behaviors influences synaptic plasticity. However, dopamine innervation and release in the hippocampus and its role during aversive behaviors are controversial. Here, we show that in vivo hippocampal synaptic plasticity in the CA3-CA1 circuit underlies contextual learning during inhibitory avoidance (IA) training. Immunohistochemistry and molecular techniques verified sparse dopaminergic innervation of the hippocampus from the midbrain. The long-term synaptic potentiation (LTP) underlying the learning of IA was assessed with a D1-like dopamine receptor agonist or antagonist in ex vivo hippocampal slices and in vivo in freely moving mice. Inhibition of D1-like dopamine receptors impaired memory of the IA task and prevented the training-induced enhancement of both ex vivo and in vivo LTP induction. The results indicate that dopamine-receptor signaling during an aversive contextual task regulates aversive memory retention and regulates associated synaptic mechanisms in the hippocampus that likely underlie learning. PMID:26904943

  14. Temporal profiles of synaptic plasticity-related signals in adult mouse hippocampus with methotrexate treatment

    Institute of Scientific and Technical Information of China (English)

    Miyoung Yang; Juhwan Kim; Sung-Ho Kim; Joong-Sun Kim; Taekyun Shin; Changjong Moon

    2012-01-01

    Methotrexate, which is used to treat many malignancies and autoimmune diseases, affects brain functions including hippocampal-dependent memory function. However, the precise mechanisms underlying methotrexate-induced hippocampal dysfunction are poorly understood. To evaluate temporal changes in synaptic plasticity-related signals, the expression and activity of N-methyl-D-aspartic acid receptor 1, calcium/calmodulin-dependent protein kinase II, extracellular signal-regulated kinase 1/2, cAMP responsive element-binding protein, glutamate receptor 1, brain-derived neurotrophic factor, and glial cell line-derived neurotrophic factor were examined in the hippocampi of adult C57BL/6 mice after methotrexate (40 mg/kg) intraperitoneal injection. Western blot analysis showed biphasic changes in synaptic plasticity-related signals in adult hippocampi following methotrexate treatment. N-methyl-D-aspartic acid receptor 1, cal-cium/calmodulin-dependent protein kinase II, and glutamate receptor 1 were acutely activated dur-ing the early phase (1 day post-injection), while extracellular signal-regulated kinase 1/2 and cAMP responsive element-binding protein activation showed biphasic increases during the early (1 day post-injection) and late phases (7-14 days post-injection). Brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor expression increased significantly during the late phase (7-14 days post-injection). Therefore, methotrexate treatment affects synaptic plasticity-related signals in the adult mouse hippocampus, suggesting that changes in synaptic plasticity-related signals may be associated with neuronal survival and plasticity-related cellular remodeling.

  15. Effects of axonal topology on the somatic modulation of synaptic outputs.

    Science.gov (United States)

    Sasaki, Takuya; Matsuki, Norio; Ikegaya, Yuji

    2012-02-22

    Depolarization of the neuronal soma augments synaptic output onto postsynaptic neurons via long-range, axonal cable properties. Here, we report that the range of this somatic influence is spatially restricted by not only axonal path length but also a branching-dependent decrease in axon diameter. Cell-attached recordings of action potentials (APs) from multiple axon branches of a rat hippocampal CA3 pyramidal cell revealed that an AP was broadened following a 20 mV depolarization of the soma and reverted to a normal width during propagation down the axon. The narrowing of the AP depended on the distance traveled by the AP and on the number of axon branch points through which the AP passed. These findings were confirmed by optical imaging of AP-induced calcium elevations in presynaptic boutons, suggesting that the somatic membrane potential modifies synaptic outputs near the soma but not long-projection outputs. Consistent with this prediction, whole-cell recordings from synaptically connected neurons revealed that depolarization of presynaptic CA3 pyramidal cells facilitated synaptic transmission to nearby CA3 pyramidal cells, but not to distant pyramidal cells in CA3 or CA1. Therefore, axonal geometry enables the differential modulation of synaptic output depending on target location.

  16. Progress on the biphase turbine at Cerro Prieto

    Energy Technology Data Exchange (ETDEWEB)

    Cerini, D.; Hays, L.; Studhalter, W. [Douglas Energy Company, Placentia, CA (United States)

    1997-12-31

    The status of a Biphase turbine power plant being installed at the Cerro Prieto geothermal field is presented. The major modules for the power plant are completed except for a back pressure steam turbine. The power plant will be started in April 1997 with the Biphase turbine alone followed by the addition of the steam turbine module two months later. The current power plant performance level is 2780 kWe due to a decline in the well. An increase in power output to 4060 kWe by adding the flow from another well is planned. The addition of five Biphase power plants with a total power output of 21.2 megawatts is described.

  17. In situ synthesis of silicon-substituted biphasic calcium phosphate and their performance in vitro

    Science.gov (United States)

    Song, Chang-Weon; Kim, Tae-Wan; Kim, Dong-Hyun; Jin, Hyeong-Ho; Hwang, Kyu-Hong; Lee, Jong Kook; Park, Hong-Chae; Yoon, Seog-Young

    2012-01-01

    In situ preparation of silicon (Si) substituted biphasic calcium phosphate (BCP) of hydroxyapatite (HAp)/ β-tricalcium phosphate (β-TCP) were carried out through aqueous co-precipitation method. The concentrations of added silicon were varied with the phosphor in order to obtain constant Ca/(P+Si) ratios of 1.602. X-ray diffraction (XRD) and Fourier transformed infrared (FTIR) spectroscopy were used to characterize the structure of synthesized silicon substituted BCP powders. The characterization revealed that the formation of biphasic mixtures of different HAp/ β-TCP ratios was dependent on the content of silicon. After immersing in Hanks' balanced salt solution (HBSS) for 1 week, 3 wt% silicon substituted BCP powders were degraded and precipitation started to be formed with small granules consisting of number of flake-like crystal onto the surface of synthesized powders. In the case of 1 wt% silicon substituted BCP powders, the degradation behavior was detected after immersion in HBSS for 3 weeks. On the other hand, silicon unsubtituted BCP powders were not degraded even after that duration. On the basis of these results, silicon substituted BCP is able to develop a new apatite phase on the surface in contact with physiological fluids faster than BCP does. This enhanced reactivity resulted in reduction for the stability of the β-TCP structure due to SiO4 tetrahedral distortion and disorder at the hydroxyl site when silicon incorporates into BCP.

  18. Synaptic determinants of Rett syndrome

    Directory of Open Access Journals (Sweden)

    Elena M B Boggio

    2010-08-01

    Full Text Available There is mounting evidence showing that the structural and molecular organization of synaptic connections are affected both in human patients and in animal models of neurological and psychiatric diseases. As a consequence of these experimental observations, it has been introduced the concept of synapsopathies, a notion describing brain disorders of synaptic function and plasticity. A close correlation between neurological diseases and synaptic abnormalities is especially relevant for those syndromes including also mental retardation in their symptomatology, such as Rett Syndrome (RS. RS (MIM312750 is an X-linked dominant neurological disorder that is caused, in the majority of cases by mutations in methyl-CpG-binding protein 2 (MeCP2. This review will focus on the current knowledge of the synaptic alterations produced by mutations of the gene MeCP2 in mouse models of RS and will highlight prospects experimental therapies currently in use. Different experimental approaches have revealed that RS could be the consequence of an impairment in the homeostasis of synaptic transmission in specific brain regions. Indeed, several forms of experience-induced neuronal plasticity are impaired in the absence of MeCP2. Based on the results presented in this review, it is reasonable to propose that understanding how the brain is affected by diseases such as RS is at reach. This effort will bring us closer to identify the neurobiological bases of human cognition.

  19. Therapeutic hypothermia protects against ischemia-induced impairment of synaptic plasticity following juvenile cardiac arrest in sex-dependent manner.

    Science.gov (United States)

    Dietz, R M; Deng, G; Orfila, J E; Hui, X; Traystman, R J; Herson, P S

    2016-06-14

    Pediatric cardiac arrest (CA) often leads to poor neurologic outcomes, including deficits in learning and memory. The only approved treatment for CA is therapeutic hypothermia, although its utility in the pediatric population remains unclear. This study analyzed the effect of mild therapeutic hypothermia after CA in juvenile mice on hippocampal neuronal injury and the cellular model of learning and memory, termed long-term potentiation (LTP). Juvenile mice were subjected to cardiac arrest and cardiopulmonary resuscitation (CA/CPR) followed by normothermia (37°C) and hypothermia (30°C, 32°C). Histological injury of hippocampal CA1 neurons was performed 3days after resuscitation using hematoxylin and eosin (H&E) staining. Field excitatory post-synaptic potentials (fEPSPs) were recorded from acute hippocampal slices 7days after CA/CPR to determine LTP. Synaptic function was impaired 7days after CA/CPR. Mice exposed to hypothermia showed equivalent neuroprotection, but exhibited sexually dimorphic protection against ischemia-induced impairment of LTP. Hypothermia (32°C) protects synaptic plasticity more effectively in females, with males requiring a deeper level of hypothermia (30°C) for equivalent protection. In conclusion, male and female juvenile mice exhibit equivalent neuronal injury following CA/CPR and hypothermia protects both males and females. We made the surprising finding that juvenile mice have a sexually dimorphic response to mild therapeutic hypothermia protection of synaptic function, where males may need a deeper level of hypothermia for equivalent synaptic protection. PMID:27033251

  20. Dynamic inhibition of excitatory synaptic transmission by astrocyte-derived ATP in hippocampal cultures

    OpenAIRE

    Koizumi, Schuichi; Fujishita, Kayoko; Tsuda, Makoto; Shigemoto-Mogami, Yukari; Inoue, Kazuhide

    2003-01-01

    Originally ascribed passive roles in the CNS, astrocytes are now known to have an active role in the regulation of synaptic transmission. Neuronal activity can evoke Ca2+ transients in astrocytes, and Ca2+ transients in astrocytes can evoke changes in neuronal activity. The excitatory neurotransmitter glutamate has been shown to mediate such bidirectional communication between astrocytes and neurons. We demonstrate here that ATP, a primary mediator of intercellular Ca2+ signaling among astroc...

  1. Effects of baclofen on synaptically-induced cell firing in the rat hippocampal slice.

    OpenAIRE

    Ault, B.; Nadler, J V

    1983-01-01

    The effects of baclofen on the synaptically-induced firing of pyramidal and granule cell populations were tested in the rat hippocampal slice. Population spikes were evoked by stimulating excitatory pathways in the presence and absence of bath-applied drug. (+/-)-Baclofen (20 microM) completely blocked the firing of CA1 or CA3 hippocampal pyramidal cells subsequent to stimulation of projections that originate in area CA3. In contrast, the firing of dentate granule cells evoked by stimulation ...

  2. Preparation and in vitro bioactivity of hydroxyapatite/solgel glass biphasic material.

    Science.gov (United States)

    Ragel, C V; Vallet-Regí, M; Rodríguez-Lorenzo, L M

    2002-04-01

    Hydroxyapatite/solgel glass biphasic material has been obtained in order to improve the bioactivity of the hydroxyapatite (OHAp). A mixture of stoichiometric OHAp and the precursor gel of a solgel glass, with nominal composition in mol% CaO-26, SiO2-70, P205-4, has been prepared. The amounts of components used have been selected to obtain a final relationship for OHAp/solgel glass of 60/40 on heating. Two different thermal treatments have been used: (i) 700 degrees C, temperature of solgel glass stabilisation and (ii) 1000 degrees C, lower temperature of hydroxyapatite sintering. The bioactivity of the resulting materials has been examined in vitro by immersion in simulated body fluid at 37 degrees C. The results obtained show that both materials are bioactive. The apatite-like layer grown is greater for the new materials than for the OHAp and the solgel glass themselves. PMID:11950057

  3. Intrinsically Stretchable Biphasic (Solid–Liquid) Thin Metal Films

    OpenAIRE

    Hirsch, Arthur Edouard; Michaud, Hadrien Olivier; Gerratt, Aaron Powers; Mulatier, Séverine; Lacour, Stéphanie

    2016-01-01

    Stretchable biphasic conductors are formed by physical vapor deposition of gallium onto an alloying metal film. The properties of the photolithography-compatible thin metal films are highlighted by low sheet resistance (0.5 Ω sq−1) and large stretchability (400%). This novel approach to deposit and pattern liquid metals enables extremely robust, multilayer and soft circuits, sensors, and actuators.

  4. Intrinsically Stretchable Biphasic (Solid-Liquid) Thin Metal Films.

    Science.gov (United States)

    Hirsch, Arthur; Michaud, Hadrien O; Gerratt, Aaron P; de Mulatier, Séverine; Lacour, Stéphanie P

    2016-06-01

    Stretchable biphasic conductors are formed by physical vapor deposition of gallium onto an alloying metal film. The properties of the photolithography-compatible thin metal films are highlighted by low sheet resistance (0.5 Ω sq(-1) ) and large stretchability (400%). This novel approach to deposit and pattern liquid metals enables extremely robust, multilayer and soft circuits, sensors, and actuators. PMID:26923313

  5. Calcium/calmodulin-dependent kinase IV contributes to translation-dependent early synaptic potentiation in the anterior cingulate cortex of adult mice

    Directory of Open Access Journals (Sweden)

    Toyoda Hiroki

    2010-09-01

    Full Text Available Abstract Calcium/calmodulin-dependent kinase IV (CaMKIV phosphorylates the major transcription factor, cyclic AMP-responsive element binding protein (CREB, which plays key roles in synaptic plasticity and memory consolidation. Our previous study showed that long-term potentiation (LTP in the anterior cingulate cortex (ACC was significantly enhanced in transgenic mice overexpressing CaMKIV. Considering that the CaMKIV-CREB pathway plays a central role in the protein synthesis-dependent LTP, it is possible that upregulation of CaMKIV contributes to enhancement of LTP by promoting protein synthesis. To test this possibility, we examined the effects of transcription and translation inhibitors on synaptic potentiation induced by pairing of synaptic activity with postsynaptic depolarization (paired training in ACC pyramidal neurons of wild-type and CaMKIV transgenic mice. We found that synaptic potentiation induced by paired training was partially inhibited by transcription or translation inhibitors both in wild-type and CaMKIV transgenic mice; the extent of inhibition was markedly larger in the CaMKIV transgenic mice than in the wild-type mice. Biochemical and immunohistochemical studies revealed that CaMKIV was distributed in the membrane, cytosol and nucleus of ACC neurons. Our results reveal in the first time a transcription- and translation-dependent component of early synaptic LTP in adult ACC synapses, and demonstrate that CaMKIV enhances early synaptic potentiation by activating new protein synthesis.

  6. Inflammation subverts hippocampal synaptic plasticity in experimental multiple sclerosis.

    Directory of Open Access Journals (Sweden)

    Robert Nisticò

    Full Text Available Abnormal use-dependent synaptic plasticity is universally accepted as the main physiological correlate of memory deficits in neurodegenerative disorders. It is unclear whether synaptic plasticity deficits take place during neuroinflammatory diseases, such as multiple sclerosis (MS and its mouse model, experimental autoimmune encephalomyelitis (EAE. In EAE mice, we found significant alterations of synaptic plasticity rules in the hippocampus. When compared to control mice, in fact, hippocampal long-term potentiation (LTP induction was favored over long-term depression (LTD in EAE, as shown by a significant rightward shift in the frequency-synaptic response function. Notably, LTP induction was also enhanced in hippocampal slices from control mice following interleukin-1β (IL-1β perfusion, and both EAE and IL-1β inhibited GABAergic spontaneous inhibitory postsynaptic currents (sIPSC without affecting glutamatergic transmission and AMPA/NMDA ratio. EAE was also associated with selective loss of GABAergic interneurons and with reduced gamma-frequency oscillations in the CA1 region of the hippocampus. Finally, we provided evidence that microglial activation in the EAE hippocampus was associated with IL-1β expression, and hippocampal slices from control mice incubated with activated microglia displayed alterations of GABAergic transmission similar to those seen in EAE brains, through a mechanism dependent on enhanced IL-1β signaling. These data may yield novel insights into the basis of cognitive deficits in EAE and possibly of MS.

  7. Biphasic survival analysis of trypanotolerance QTL in mice.

    Science.gov (United States)

    Koudandé, O D; Thomson, P C; Bovenhuis, H; Iraqi, F; Gibson, J P; van Arendonk, J A M

    2008-04-01

    A marker-assisted introgression (MAI) experiment was conducted to transfer trypanotolerance quantitative trait loci (QTL) from a donor mouse strain, C57BL/6, into a recipient mouse strain, A/J. The objective was to assess the effect of three previously identified chromosomal regions on mouse chromosomes 1 (MMU1), 5 (MMU5) and 17 (MMU17) in different genetic backgrounds on the survival pattern following infection with Trypanosoma congolense. An exploratory data analysis revealed a biphasic pattern of time to death, with highly distinct early and late mortality phases. In this paper, we present survival analysis methods that account for the biphasic mortality pattern and results of reanalyzing the data from the MAI experiment. The analysis with a Weibull mixture model confirmed the biphasic pattern of time to death. Mortality phase, an unobserved variable, appears to be an important factor influencing survival time and is modeled as a binary outcome variable using logistic regression analysis. Accounting for this biphasic pattern in the analysis reveals that a previously observed sex effect on average survival is rather an effect on proportion of mice in the two mortality phases. The C57BL/6 (donor) QTL alleles on MMU1 and MMU17 act dominantly in the late mortality phase while the A/J (recipient) QTL allele on MMU17 acts dominantly in the early mortality phase. From this study, we found clear evidence for a biphasic survival pattern and provided models for its analysis. These models can also be used when studying defense mechanisms against other pathogens. Finally, these approaches provide further information on the nature of gene actions. PMID:18253157

  8. PKMzeta inhibition reverses learning-induced increases in hippocampal synaptic strength and memory during trace eyeblink conditioning.

    Directory of Open Access Journals (Sweden)

    Noelia Madroñal

    Full Text Available A leading candidate in the process of memory formation is hippocampal long-term potentiation (LTP, a persistent enhancement in synaptic strength evoked by the repetitive activation of excitatory synapses, either by experimental high-frequency stimulation (HFS or, as recently shown, during actual learning. But are the molecular mechanisms for maintaining synaptic potentiation induced by HFS and by experience the same? Protein kinase Mzeta (PKMzeta, an autonomously active atypical protein kinase C isoform, plays a key role in the maintenance of LTP induced by tetanic stimulation and the storage of long-term memory. To test whether the persistent action of PKMzeta is necessary for the maintenance of synaptic potentiation induced after learning, the effects of ZIP (zeta inhibitory peptide, a PKMzeta inhibitor, on eyeblink-conditioned mice were studied. PKMzeta inhibition in the hippocampus disrupted both the correct retrieval of conditioned responses (CRs and the experience-dependent persistent increase in synaptic strength observed at CA3-CA1 synapses. In addition, the effects of ZIP on the same associative test were examined when tetanic LTP was induced at the hippocampal CA3-CA1 synapse before conditioning. In this case, PKMzeta inhibition both reversed tetanic LTP and prevented the expected LTP-mediated deleterious effects on eyeblink conditioning. Thus, PKMzeta inhibition in the CA1 area is able to reverse both the expression of trace eyeblink conditioned memories and the underlying changes in CA3-CA1 synaptic strength, as well as the anterograde effects of LTP on associative learning.

  9. Phosphorylation of AMPA receptors is required for sensory deprivation-induced homeostatic synaptic plasticity.

    Science.gov (United States)

    Goel, Anubhuti; Xu, Linda W; Snyder, Kevin P; Song, Lihua; Goenaga-Vazquez, Yamila; Megill, Andrea; Takamiya, Kogo; Huganir, Richard L; Lee, Hey-Kyoung

    2011-01-01

    Sensory experience, and the lack thereof, can alter the function of excitatory synapses in the primary sensory cortices. Recent evidence suggests that changes in sensory experience can regulate the synaptic level of Ca(2+)-permeable AMPA receptors (CP-AMPARs). However, the molecular mechanisms underlying such a process have not been determined. We found that binocular visual deprivation, which is a well-established in vivo model to produce multiplicative synaptic scaling in visual cortex of juvenile rodents, is accompanied by an increase in the phosphorylation of AMPAR GluR1 (or GluA1) subunit at the serine 845 (S845) site and the appearance of CP-AMPARs at synapses. To address the role of GluR1-S845 in visual deprivation-induced homeostatic synaptic plasticity, we used mice lacking key phosphorylation sites on the GluR1 subunit. We found that mice specifically lacking the GluR1-S845 site (GluR1-S845A mutants), which is a substrate of cAMP-dependent kinase (PKA), show abnormal basal excitatory synaptic transmission and lack visual deprivation-induced homeostatic synaptic plasticity. We also found evidence that increasing GluR1-S845 phosphorylation alone is not sufficient to produce normal multiplicative synaptic scaling. Our study provides concrete evidence that a GluR1 dependent mechanism, especially S845 phosphorylation, is a necessary pre-requisite step for in vivo homeostatic synaptic plasticity.

  10. Phosphorylation of AMPA receptors is required for sensory deprivation-induced homeostatic synaptic plasticity.

    Directory of Open Access Journals (Sweden)

    Anubhuti Goel

    Full Text Available Sensory experience, and the lack thereof, can alter the function of excitatory synapses in the primary sensory cortices. Recent evidence suggests that changes in sensory experience can regulate the synaptic level of Ca(2+-permeable AMPA receptors (CP-AMPARs. However, the molecular mechanisms underlying such a process have not been determined. We found that binocular visual deprivation, which is a well-established in vivo model to produce multiplicative synaptic scaling in visual cortex of juvenile rodents, is accompanied by an increase in the phosphorylation of AMPAR GluR1 (or GluA1 subunit at the serine 845 (S845 site and the appearance of CP-AMPARs at synapses. To address the role of GluR1-S845 in visual deprivation-induced homeostatic synaptic plasticity, we used mice lacking key phosphorylation sites on the GluR1 subunit. We found that mice specifically lacking the GluR1-S845 site (GluR1-S845A mutants, which is a substrate of cAMP-dependent kinase (PKA, show abnormal basal excitatory synaptic transmission and lack visual deprivation-induced homeostatic synaptic plasticity. We also found evidence that increasing GluR1-S845 phosphorylation alone is not sufficient to produce normal multiplicative synaptic scaling. Our study provides concrete evidence that a GluR1 dependent mechanism, especially S845 phosphorylation, is a necessary pre-requisite step for in vivo homeostatic synaptic plasticity.

  11. The interplay between neuronal activity and actin dynamics mimic the setting of an LTD synaptic tag.

    Science.gov (United States)

    Szabó, Eszter C; Manguinhas, Rita; Fonseca, Rosalina

    2016-09-21

    Persistent forms of plasticity, such as long-term depression (LTD), are dependent on the interplay between activity-dependent synaptic tags and the capture of plasticity-related proteins. We propose that the synaptic tag represents a structural alteration that turns synapses permissive to change. We found that modulation of actin dynamics has different roles in the induction and maintenance of LTD. Inhibition of either actin depolymerisation or polymerization blocks LTD induction whereas only the inhibition of actin depolymerisation blocks LTD maintenance. Interestingly, we found that actin depolymerisation and CaMKII activation are involved in LTD synaptic-tagging and capture. Moreover, inhibition of actin polymerisation mimics the setting of a synaptic tag, in an activity-dependent manner, allowing the expression of LTD in non-stimulated synapses. Suspending synaptic activation also restricts the time window of synaptic capture, which can be restored by inhibiting actin polymerization. Our results support our hypothesis that modulation of the actin cytoskeleton provides an input-specific signal for synaptic protein capture.

  12. ATP from synaptic terminals and astrocytes regulates NMDA receptors and synaptic plasticity through PSD-95 multi-protein complex.

    Science.gov (United States)

    Lalo, U; Palygin, O; Verkhratsky, A; Grant, S G N; Pankratov, Y

    2016-01-01

    Recent studies highlighted the importance of astrocyte-secreted molecules, such as ATP, for the slow modulation of synaptic transmission in central neurones. Biophysical mechanisms underlying the impact of gliotransmitters on the strength of individual synapse remain, however, unclear. Here we show that purinergic P2X receptors can bring significant contribution to the signalling in the individual synaptic boutons. ATP released from astrocytes facilitates a recruitment of P2X receptors into excitatory synapses by Ca(2+)-dependent mechanism. P2X receptors, co-localized with NMDA receptors in the excitatory synapses, can be activated by ATP co-released with glutamate from pre-synaptic terminals and by glia-derived ATP. An activation of P2X receptors in turn leads to down-regulation of postsynaptic NMDA receptors via Ca(2+)-dependent de-phosphorylation and interaction with PSD-95 multi-protein complex. Genetic deletion of the PSD-95 or P2X4 receptors obliterated ATP-mediated down-regulation of NMDA receptors. Impairment of purinergic modulation of NMDA receptors in the PSD-95 mutants dramatically decreased the threshold of LTP induction and increased the net magnitude of LTP. Our findings show that synergistic action of glia- and neurone-derived ATP can pre-modulate efficacy of excitatory synapses and thereby can have an important role in the glia-neuron communications and brain meta-plasticity. PMID:27640997

  13. Super-resolution microscopy of the synaptic active zone

    Directory of Open Access Journals (Sweden)

    Nadine eEhmann

    2015-01-01

    Full Text Available Brain function relies on accurate information transfer at chemical synapses. At the presynaptic active zone (AZ a variety of specialised proteins are assembled to complex architectures, which set the basis for speed, precision and plasticity of synaptic transmission.Calcium (Ca2+ channels are pivotal for the initiation of excitation-secretion coupling and, correspondingly, capture a central position at the AZ. Combining quantitative functional studies with modelling approaches has provided predictions of channel properties, numbers and even positions on the nanometre scale. However, elucidating the nanoscopic organisation of the surrounding protein network requires direct ultrastructural access. Without this information, knowledge of molecular synaptic structure-function relationships remains incomplete. Recently, super-resolution microscopy techniques have begun to enter the neurosciences. These approaches combine high spatial resolution with the molecular specificity of fluorescence microscopy. Here, we discuss how super-resolution microscopy can be used to obtain information on the organisation of AZ proteins.

  14. Different pH-dependencies of the two synaptic adhesion molecules N-cadherin and cadherin-11 and the possible functional implication for long-term potentiation

    DEFF Research Database (Denmark)

    Baumgartner, Werner; Osmanagic, Armin; Gebhard, Marita;

    2013-01-01

    Ca(2+) -dependent adhesion molecules, cadherins, localised at synaptic sites are critically involved in long-term potentiation (LTP). N-cadherin is thought to promote LTP whereas cadherin-11 seems to counteract LTP. Since high synaptic activity is accompanied by local transient changes of the p...

  15. Thermoreversible (Ionic-Liquid-Based) Aqueous Biphasic Systems.

    Science.gov (United States)

    Passos, Helena; Luís, Andreia; Coutinho, João A P; Freire, Mara G

    2016-02-04

    The ability to induce reversible phase transitions between homogeneous solutions and biphasic liquid-liquid systems, at pre-defined and suitable operating temperatures, is of crucial relevance in the design of separation processes. Ionic-liquid-based aqueous biphasic systems (IL-based ABS) have demonstrated superior performance as alternative extraction platforms, and their thermoreversible behaviour is here disclosed by the use of protic ILs. The applicability of the temperature-induced phase switching is further demonstrated with the complete extraction of two value-added proteins, achieved in a single-step. It is shown that these temperature-induced mono(bi)phasic systems are significantly more versatile than classical liquid-liquid systems which are constrained by their critical temperatures. IL-based ABS allow to work in a wide range of temperatures and compositions which can be tailored to fit the requirements of a given separation process.

  16. Thermoreversible (Ionic-Liquid-Based) Aqueous Biphasic Systems

    Science.gov (United States)

    Passos, Helena; Luís, Andreia; Coutinho, João A. P.; Freire, Mara G.

    2016-02-01

    The ability to induce reversible phase transitions between homogeneous solutions and biphasic liquid-liquid systems, at pre-defined and suitable operating temperatures, is of crucial relevance in the design of separation processes. Ionic-liquid-based aqueous biphasic systems (IL-based ABS) have demonstrated superior performance as alternative extraction platforms, and their thermoreversible behaviour is here disclosed by the use of protic ILs. The applicability of the temperature-induced phase switching is further demonstrated with the complete extraction of two value-added proteins, achieved in a single-step. It is shown that these temperature-induced mono(bi)phasic systems are significantly more versatile than classical liquid-liquid systems which are constrained by their critical temperatures. IL-based ABS allow to work in a wide range of temperatures and compositions which can be tailored to fit the requirements of a given separation process.

  17. Biphasic positive airway pressure ventilation (PeV+) in children

    OpenAIRE

    Jaarsma, Anneke S; Knoester, Hennie; van Rooyen, Frank; Bos, Albert P.

    2001-01-01

    Background: Biphasic positive airway pressure (BIPAP) (also known as PeV+) is a mode of ventilation with cycling variations between two continuous positive airway pressure levels. In adults this mode of ventilation is effective and is being accepted with a decrease in need for sedatives because of the ability to breathe spontaneously during the entire breathing cycle. We studied the use of BIPAP in infants and children. Methods: We randomized 18 patients with respiratory failure for ventilati...

  18. Comparison between FEBio and Abaqus for biphasic contact problems

    OpenAIRE

    Q Meng; Jin, Z.; J. Fisher; Wilcox, R

    2013-01-01

    Articular cartilage plays an important role in the function of diarthrodial joints. Computational methods have been used to study the biphasic mechanics of cartilage, and Abaqus has been one of the most widely used commercial software packages for this purpose. A newly developed open-source finite element solver, FEBio, has been developed specifically for biomechanical applications. The aim of this study was to undertake a direct comparison between FEBio and Abaqus for some practical contact ...

  19. The relative contribution of NMDARs to excitatory postsynaptic currents is controlled by Ca2+-induced inactivation.

    Directory of Open Access Journals (Sweden)

    Fliza eValiullina

    2016-01-01

    Full Text Available NMDA receptors (NMDARs are important mediators of excitatory synaptic transmission and plasticity. A hallmark of these channels is their high permeability to Ca2+. At the same time, they are themselves inhibited by the elevation of intracellular Ca2+ concentration. It is unclear however, whether the Ca2+ entry associated with single NMDAR mediated synaptic events is sufficient to self-inhibit their activation. Such auto-regulation would have important effects on the dynamics of synaptic excitation in several central networks. Therefore, we studied NMDAR-mediated synaptic currents in mouse hippocampal CA1 pyramidal neurons. Postsynaptic responses to subthreshold Schaffer collateral stimulation depended strongly on the absence or presence of intracellular Ca2+ buffers. Loading of pyramidal cells with exogenous Ca2+ buffers increased the amplitude and decay time of NMDAR mediated EPSCs (EPSP and prolonged the time window for action potential generation.Our data indicate that the Ca2+ influx mediated by unitary synaptic events is sufficient to produce detectable self-inhibition of NMDARs even at a physiological Mg2+ concentration. Therefore, the contribution of NMDARs to synaptic excitation is strongly controlled by both previous synaptic activity as well as by the Ca2+ buffer capacity of postsynaptic neurons.

  20. Actinide recovery using aqueous biphasic extraction: Initial developmental studies

    Energy Technology Data Exchange (ETDEWEB)

    Chaiko, D.J.; Mensah-Biney, R.; Mertz, C.J.; Rollins, A.N.

    1992-08-01

    Aqueous biphasic extraction systems are being developed to treat radioactive wastes. The separation technique involves the selective partitioning of either solutes or colloid-size particles between two scible aqueous phases. Wet grinding of plutonium residues to an average particle size of one micron will be used to liberate the plutonium from the bulk of the particle matrix. The goal is to produce a plutonium concentrate that will integrate with existing and developing chemical recovery processes. Ideally, the process would produce a nonTRU waste stream. Coupling physical beneficiation with chemical processing will result in a substantial reduction in the volume of mixed wastes generated from dissolution recovery processes. As part of this program, we will also explore applications of aqueous biphasic extraction that include the separation and recovery of dissolved species such as metal ions and water-soluble organics. The expertise and data generated in this work will form the basis for developing more cost-effective processes for handling waste streams from environmental restoration and waste management activities within the DOE community. This report summarizes the experimental results obtained during the first year of this effort. Experimental efforts were focused on elucidating the surface and solution chemistry variables which govern partitioning behavior of plutonium and silica in aqueous biphasic extraction systems. Additional efforts were directed toward the development of wet grinding methods for producing ultrafine particles with diameters of one micron or less.

  1. Characterization and biocompatibility of fluoridated biphasic calcium phosphate ceramics

    Energy Technology Data Exchange (ETDEWEB)

    Zhu, Z.L. [State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041 (China); Yu, H.Y. [State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041 (China)], E-mail: yhyang6812@tfol.com; Zeng, Q. [Institute for Nanobiomedical Technology and Membrane Biology, Sichuan University, Chengdu 610041 (China); He, H.W. [State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041 (China)

    2008-11-15

    Biphasic calcium phosphate ceramics (BCP) has been widely used in tooth and bone implants due to its excellent biocompatibility. Incorporation of fluorine ions in BCP has drawn much attention because of the beneficial role played by the fluorine ions in bone and tooth growth. The aim of this study was to obtain fluoridated biphasic calcium phosphate (FBCP) by immersing BCP into saturated ZnF{sub 2} solution with F{sup -} concentration of 3500 mg/l at different times. The phase and incorporation of fluoride into BCP were characterized by X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS) and scanning electron microscope (SEM). The biomineralization and influence of FBCP on osteoblastic behavior were evaluated and compared with that of biphasic calcium phosphate (BCP). The results exhibited that the phase evolution of the BCP was affected by the fluoride incorporation and the FBCP significantly improved the differentiation and proliferation of osteoblasts. These findings suggest that the FBCP would be very useful as a bone reconstructive material.

  2. Actinide recovery using aqueous biphasic extraction: Initial developmental studies

    International Nuclear Information System (INIS)

    Aqueous biphasic extraction systems are being developed to treat radioactive wastes. The separation technique involves the selective partitioning of either solutes or colloid-size particles between two scible aqueous phases. Wet grinding of plutonium residues to an average particle size of one micron will be used to liberate the plutonium from the bulk of the particle matrix. The goal is to produce a plutonium concentrate that will integrate with existing and developing chemical recovery processes. Ideally, the process would produce a nonTRU waste stream. Coupling physical beneficiation with chemical processing will result in a substantial reduction in the volume of mixed wastes generated from dissolution recovery processes. As part of this program, we will also explore applications of aqueous biphasic extraction that include the separation and recovery of dissolved species such as metal ions and water-soluble organics. The expertise and data generated in this work will form the basis for developing more cost-effective processes for handling waste streams from environmental restoration and waste management activities within the DOE community. This report summarizes the experimental results obtained during the first year of this effort. Experimental efforts were focused on elucidating the surface and solution chemistry variables which govern partitioning behavior of plutonium and silica in aqueous biphasic extraction systems. Additional efforts were directed toward the development of wet grinding methods for producing ultrafine particles with diameters of one micron or less

  3. Open Syntaxin Docks Synaptic Vesicles

    OpenAIRE

    Marc Hammarlund; Mark T Palfreyman; Shigeki Watanabe; Shawn Olsen; Erik M. Jorgensen

    2007-01-01

    Author Summary Like Olympic swimmers crouched on their starting blocks, synaptic vesicles prepare for fusion with the neuronal plasma membrane long before the starting gun fires. This preparation enables vesicles to fuse rapidly, synchronously, and in the correct place when the signal finally arrives. A well-known but poorly understood part of vesicle preparation is docking, in which vesicles prepare for release by attaching to the plasma membrane at the eventual site of release. Here, we out...

  4. Synaptic vesicle pools: an update

    Directory of Open Access Journals (Sweden)

    Annette Denker

    2010-10-01

    Full Text Available During the last few decades synaptic vesicles have been assigned to a variety of functional and morphological classes or pools. We have argued in the past (Rizzoli SO and Betz WJ, 2005, Synaptic vesicle pools, Nat. Rev. Neurosci. 6, 57-69 that synaptic activity in several preparations is accounted for by the function of three vesicle pools: the readily releasable pool (docked at active zones and ready to go upon stimulation, the recycling pool (scattered throughout the nerve terminals and recycling upon moderate stimulation, and finally the reserve pool (occupying most of the vesicle clusters and only recycling upon strong stimulation. We discuss here the advancements in the vesicle pool field which took place in the ensuing years, focusing on the behavior of different pools under both strong stimulation and physiological activity. Several new findings have enhanced the three-pool model, with, for example, the disparity between recycling and reserve vesicles being underlined by the observation that the former are mobile, while the latter are fixed. Finally, a number of altogether new concepts have also evolved such as the current controversy on the identity of the spontaneously recycling vesicle pool.

  5. ATP hydrolysis is critically required for function of CaV1.3 channels in cochlear inner hair cells via fueling Ca2+ clearance.

    Science.gov (United States)

    Weiler, Simon; Krinner, Stefanie; Wong, Aaron B; Moser, Tobias; Pangršič, Tina

    2014-05-14

    Sound encoding is mediated by Ca(2+) influx-evoked release of glutamate at the ribbon synapse of inner hair cells. Here we studied the role of ATP in this process focusing on Ca(2+) current through CaV1.3 channels and Ca(2+) homeostasis in mouse inner hair cells. Patch-clamp recordings and Ca(2+) imaging demonstrate that hydrolyzable ATP is essential to maintain synaptic Ca(2+) influx in inner hair cells via fueling Ca(2+)-ATPases to avoid an increase in cytosolic [Ca(2+)] and subsequent Ca(2+)/calmodulin-dependent inactivation of CaV1.3 channels.

  6. Molecular underpinnings of synaptic vesicle pool heterogeneity.

    Science.gov (United States)

    Crawford, Devon C; Kavalali, Ege T

    2015-04-01

    Neuronal communication relies on chemical synaptic transmission for information transfer and processing. Chemical neurotransmission is initiated by synaptic vesicle fusion with the presynaptic active zone resulting in release of neurotransmitters. Classical models have assumed that all synaptic vesicles within a synapse have the same potential to fuse under different functional contexts. In this model, functional differences among synaptic vesicle populations are ascribed to their spatial distribution in the synapse with respect to the active zone. Emerging evidence suggests, however, that synaptic vesicles are not a homogenous population of organelles, and they possess intrinsic molecular differences and differential interaction partners. Recent studies have reported a diverse array of synaptic molecules that selectively regulate synaptic vesicles' ability to fuse synchronously and asynchronously in response to action potentials or spontaneously irrespective of action potentials. Here we discuss these molecular mediators of vesicle pool heterogeneity that are found on the synaptic vesicle membrane, on the presynaptic plasma membrane, or within the cytosol and consider some of the functional consequences of this diversity. This emerging molecular framework presents novel avenues to probe synaptic function and uncover how synaptic vesicle pools impact neuronal signaling.

  7. Traumatic brain injury impairs synaptic plasticity in hippocampus in rats

    Institute of Scientific and Technical Information of China (English)

    ZHANG Bao-liang; CHEN Xin; TAN Tao; YANG Zhuo; CARLOS Dayao; JIANG Rong-cai; ZHANG Jian-ning

    2011-01-01

    Background Traumatic brain injury (TBl) often causes cognitive deficits and remote symptomatic epilepsy.Hippocampal regional excitability is associated with the cognitive function. However, little is known about injury-induced neuronal loss and subsequent alterations of hippocampal regional excitability. The present study was designed to determine whether TBl may impair the cellular circuit in the hippocampus.Methods Forty male Wistar rats were randomized into control (n=20) and TBl groups (n=20). Long-term potentiation,extracellular input/output curves, and hippocampal parvalbumin-immunoreactive and cholecystokinin-immunoreactive interneurons were compared between the two groups.Results TBI resulted in a significantly increased excitability in the dentate gyrus (DG), but a significantly decreased excitability in the cornu ammonis 1 (CA1) area. Using design-based stereological injury procedures, we induced interneuronal loss in the DG and CA3 subregions in the hippocampus, but not in the CA1 area.Conclusions TBl leads to the impairment of hippocampus synaptic plasticity due to the changing of interneuronal interaction. The injury-induced disruption of synaptic efficacy within the hippocampal circuit may underlie the observed cognitive deficits and symptomatic epilepsy.

  8. Synthesis, characterization and in vitro study of magnetic biphasic calcium sulfate-bioactive glass

    International Nuclear Information System (INIS)

    Calcium sulfate-bioactive glass (CSBG) composites doped with 5, 10 and 20 mol% Fe were synthesized using quick alkali sol–gel method. X-ray diffraction (XRD) data of samples heated at 700 °C revealed the presence of anhydrite, while field emission scanning electron microscopy (FESEM) and energy dispersive X-ray (EDX) characterization confirmed the formation of nano-sized CSBGs. The UV–vis studies confirmed that the main iron species in 5% Fe and 10% Fe doped CSBGs were tetrahedral Fe(III) whereas that in 20% Fe doped CSBG were extra-framework FeOx oligomers or iron oxide phases. Measurement of magnetic properties of the samples by vibrating sample magnetometer (VSM) showed very narrow hysteresis loop with zero coercivity and remanence for 10% Fe and 20% Fe doped CSBG, indicating that they are superparamagnetic in nature. All samples induced the formation of apatite layer with Ca/P ratio close to the stoichiometric HA in simulated body fluid (SBF) assessment. - Highlights: • Biphasic calcium sulphate-bioactive glass containing iron was prepared. • Composite bioglass was superparamagnetic in nature. • All samples promoted the growth of apatite layer with Ca/P close to 1.67

  9. Synthesis, characterization and in vitro study of magnetic biphasic calcium sulfate-bioactive glass

    Energy Technology Data Exchange (ETDEWEB)

    Goh, Yi-Fan; Akram, Muhammad; Alshemary, Ammar Z. [Department of Chemistry, Faculty of Science, Universiti Teknologi Malaysia, 81310 UTM Skudai, Johor, Darul Ta' zim (Malaysia); Hussain, Rafaqat, E-mail: rafaqat@kimia.fs.utm.my [Ibnu Sina Institute for Fundamental Science Studies, Universiti Teknologi Malaysia, 81310 UTM Skudai, Johor Darul Ta' zim (Malaysia)

    2015-08-01

    Calcium sulfate-bioactive glass (CSBG) composites doped with 5, 10 and 20 mol% Fe were synthesized using quick alkali sol–gel method. X-ray diffraction (XRD) data of samples heated at 700 °C revealed the presence of anhydrite, while field emission scanning electron microscopy (FESEM) and energy dispersive X-ray (EDX) characterization confirmed the formation of nano-sized CSBGs. The UV–vis studies confirmed that the main iron species in 5% Fe and 10% Fe doped CSBGs were tetrahedral Fe(III) whereas that in 20% Fe doped CSBG were extra-framework FeO{sub x} oligomers or iron oxide phases. Measurement of magnetic properties of the samples by vibrating sample magnetometer (VSM) showed very narrow hysteresis loop with zero coercivity and remanence for 10% Fe and 20% Fe doped CSBG, indicating that they are superparamagnetic in nature. All samples induced the formation of apatite layer with Ca/P ratio close to the stoichiometric HA in simulated body fluid (SBF) assessment. - Highlights: • Biphasic calcium sulphate-bioactive glass containing iron was prepared. • Composite bioglass was superparamagnetic in nature. • All samples promoted the growth of apatite layer with Ca/P close to 1.67.

  10. Regulation of synaptic connectivity by glia

    OpenAIRE

    Eroglu, Cagla; Barres, Ben A

    2010-01-01

    The human brain contains more than 100 trillion (1014) synaptic connections, which form all of its neural circuits. Neuroscientists have long been interested in how this complex synaptic web is weaved during development and remodelled during learning and disease. Recent studies have uncovered that glial cells are important regulators of synaptic connectivity. These cells are far more active than was previously thought and are powerful controllers of synapse formation, function, plasticity and...

  11. Altered hippocampus synaptic function in selenoprotein P deficient mice

    Directory of Open Access Journals (Sweden)

    Peters Melinda M

    2006-09-01

    Full Text Available Abstract Selenium is an essential micronutrient that function through selenoproteins. Selenium deficiency results in lower concentrations of selenium and selenoproteins. The brain maintains it's selenium better than other tissues under low-selenium conditions. Recently, the selenium-containing protein selenoprotein P (Sepp has been identified as a possible transporter of selenium. The targeted disruption of the selenoprotein P gene (Sepp1 results in decreased brain selenium concentration and neurological dysfunction, unless selenium intake is excessive However, the effect of selenoprotein P deficiency on the processes of memory formation and synaptic plasticity is unknown. In the present studies Sepp1(-/- mice and wild type littermate controls (Sepp1(+/+ fed a high-selenium diet (1 mg Se/kg were used to characterize activity, motor coordination, and anxiety as well as hippocampus-dependent learning and memory. Normal associative learning, but disrupted spatial learning was observed in Sepp1(-/- mice. In addition, severe alterations were observed in synaptic transmission, short-term plasticity and long-term potentiation in hippocampus area CA1 synapses of Sepp1(-/- mice on a 1 mg Se/kg diet and Sepp1(+/+ mice fed a selenium-deficient (0 mg Se/kg diet. Taken together, these data suggest that selenoprotein P is required for normal synaptic function, either through presence of the protein or delivery of required selenium to the CNS.

  12. Effect of Xiao Yao San on synaptic structural plasticity of hippocampal CA3 region of rats under multi-stress model%逍遥散对应激大鼠海马CA3区突触体结构可塑性的影响

    Institute of Scientific and Technical Information of China (English)

    徐志伟; 敖海清; 吴丽丽; 严灿; 王文竹

    2006-01-01

    目的观察逍遥散对多相性应激大鼠海马CA3区神经元结构的影响,探究逍遥散抗应激损伤大鼠海马神经突触结构可塑性的机制.方法Wistar大鼠随机分为空白对照组、病理对照1组、病理对照2组、治疗1组、治疗2组,每组10只.采用慢性多相性应激模型,透射电镜观测比较各组大鼠CA3区神经突触超微结构变化.结果病理对照1组及病理对照2组大鼠海马神经元突触的数密度[(3.066±2.032),(3.785±2.162)]与面密度[(0.100±0.056),(0.129±0.064)]较空白对照组[(5.707±2.268),(0.234±0.102)]均有明显降低(P<0.01),突触连接带的平均面积则无明显变化(P>0.05),而治疗1组与治疗2组大鼠海马神经元突触的数密度与空白对照组相比无明显差异(P>0.05);面密度则均有明显减小(P<0.01).与病理对照1组相比,治疗1组大鼠海马神经元突触的数密度与面密度均明显增大(P<0.01);治疗2组大鼠海马神经元突触的数密度明显增大(P<0.01),面密度也有所增大(P<0.05).结论多相性应激可以损伤大鼠的神经突触结构,影响突触间的相互连接.而逍遥散则可能是通过减少应激对原有的突触及突触连接的损伤,以及促进新的突触与突触连接的形成.

  13. Functionally heterogeneous synaptic vesicle pools support diverse synaptic signalling.

    Science.gov (United States)

    Chamberland, Simon; Tóth, Katalin

    2016-02-15

    Synaptic communication between neurons is a highly dynamic process involving specialized structures. At the level of the presynaptic terminal, neurotransmission is ensured by fusion of vesicles to the membrane, which releases neurotransmitter in the synaptic cleft. Depending on the level of activity experienced by the terminal, the spatiotemporal properties of calcium invasion will dictate the timing and the number of vesicles that need to be released. Diverse presynaptic firing patterns are translated to neurotransmitter release with a distinct temporal feature. Complex patterns of neurotransmitter release can be achieved when different vesicles respond to distinct calcium dynamics in the presynaptic terminal. Specific vesicles from different pools are recruited during various modes of release as the particular molecular composition of their membrane proteins define their functional properties. Such diversity endows the presynaptic terminal with the ability to respond to distinct physiological signals via the mobilization of specific subpopulation of vesicles. There are several mechanisms by which a diverse vesicle population could be generated in single presynaptic terminals, including distinct recycling pathways that utilize various adaptor proteins. Several additional factors could potentially contribute to the development of a heterogeneous vesicle pool such as specialized release sites, spatial segregation within the terminal and specialized delivery pathways. Among these factors molecular heterogeneity plays a central role in defining the functional properties of different subpopulations of vesicles. PMID:26614712

  14. Investigation of Synaptic Tagging/Capture and Cross-capture using Acute Hippocampal Slices from Rodents.

    Science.gov (United States)

    Shetty, Mahesh Shivarama; Sharma, Mahima; Hui, Neo Sin; Dasgupta, Ananya; Gopinadhan, Suma; Sajikumar, Sreedharan

    2015-01-01

    Synaptic tagging and capture (STC) and cross-tagging are two important mechanisms at cellular level that explain how synapse-specificity and associativity is achieved in neurons within a specific time frame. These long-term plasticity-related processes are the leading candidate models to study the basis of memory formation and persistence at the cellular level. Both STC and cross-tagging involve two serial processes: (1) setting of the synaptic tag as triggered by a specific pattern of stimulation, and (2) synaptic capture, whereby the synaptic tag interacts with newly synthesized plasticity-related proteins (PRPs). Much of the understanding about the concepts of STC and cross-tagging arises from the studies done in CA1 region of the hippocampus and because of the technical complexity many of the laboratories are still unable to study these processes. Experimental conditions for the preparation of hippocampal slices and the recording of stable late-LTP/LTD are extremely important to study synaptic tagging/cross-tagging. This video article describes the experimental procedures to study long-term plasticity processes such as STC and cross-tagging in the CA1 pyramidal neurons using stable, long-term field-potential recordings from acute hippocampal slices of rats. PMID:26381286

  15. Acute physiological stress promotes clustering of synaptic markers and alters spine morphology in the hippocampus.

    Directory of Open Access Journals (Sweden)

    Veronica Sebastian

    Full Text Available GluA2-containing AMPA receptors and their association with protein kinase M zeta (PKMζ and post-synaptic density-95 (PSD-95 are important for learning, memory and synaptic plasticity processes. Here we investigated these synaptic markers in the context of an acute 1h platform stress, which can disrupt spatial memory retrieval for a short-term memory on the object placement task and long-term memory retrieval on a well-learned radial arm maze task. Acute stress increased serum corticosterone and elevated the expression of synaptic PKMζ while decreasing synaptic GluA2. Using co-immunoprecipitation, we found that this stressor promotes the clustering of GluA2, PKMζ and PSD-95, which is consistent with effects reported from overexpression of PKMζ in cell culture. Because PKMζ overexpression has also been shown to induce spine maturation in culture, we examined how stress impacts synaptic markers within changing spines across various hippocampal subfields. To achieve this, we employed a new technique combining Golgi staining and immmunohistochemistry to perform 3D reconstruction of tertiary dendrites, which can be analyzed for differences in spine types and the colocalization of synaptic markers within these spines. In CA1, stress increased the densities of long-thin and mushroom spines and the colocalization of GluA2/PSD-95 within these spines. Conversely, in CA3, stress decreased the densities of filopodia and stubby spines, with a concomitant reduction in the colocalization of GluA2/PSD-95 within these spines. In the outer molecular layer (OML of the dentate gyrus (DG, stress increased both stubby and long-thin spines, together with greater GluA2/PSD-95 colocalization. These data reflect the rapid effects of stress on inducing morphological changes within specific hippocampal subfields, highlighting a potential mechanism by which stress can modulate memory consolidation and retrieval.

  16. The Streptococcus pneumoniae pilus-1 displays a biphasic expression pattern.

    Directory of Open Access Journals (Sweden)

    Gabriella De Angelis

    Full Text Available The Streptococcus pneumoniae pilus-1 is encoded by pilus islet 1 (PI-1, which has three clonal variants (clade I, II and III and is present in about 30% of clinical pneumococcal isolates. In vitro and in vivo assays have demonstrated that pilus-1 is involved in attachment to epithelial cells and virulence, as well as protection in mouse models of infection. Several reports suggest that pilus-1 expression is tightly regulated and involves the interplay of numerous genetic regulators, including the PI-1 positive regulator RlrA. In this report we provide evidence that pilus expression, when analyzed at the single-cell level in PI-1 positive strains, is biphasic. In fact, the strains present two phenotypically different sub-populations of bacteria, one that expresses the pilus, while the other does not. The proportions of these two phenotypes are variable among the strains tested and are not influenced by genotype, serotype, growth conditions, colony morphology or by the presence of antibodies directed toward the pilus components. Two sub-populations, enriched in pilus expressing or not expressing bacteria were obtained by means of colony selection and immuno-detection methods for five strains. PI-1 sequencing in the two sub-populations revealed the absence of mutations, thus indicating that the biphasic expression observed is not due to a genetic modification within PI-1. Microarray expression profile and western blot analyses on whole bacterial lysates performed comparing the two enriched sub-populations, revealed that pilus expression is regulated at the transcriptional level (on/off regulation, and that there are no other genes, in addition to those encoded by PI-1, concurrently regulated across the strains tested. Finally, we provide evidence that the over-expression of the RrlA positive regulator is sufficient to induce pilus expression in pilus-1 negative bacteria. Overall, the data presented here suggest that the observed biphasic pilus

  17. A new kinetic biphasic approach applied to biodiesel process intensification

    Energy Technology Data Exchange (ETDEWEB)

    Russo, V.; Tesser, R.; Di Serio, M.; Santacesaria, E. [Naples Univ. (Italy). Dept. of Chemistry

    2012-07-01

    Many different papers have been published on the kinetics of the transesterification of vegetable oil with methanol, in the presence of alkaline catalysts to produce biodiesel. All the proposed approaches are based on the assumption of a pseudo-monophasic system. The consequence of these approaches is that some experimental aspects cannot be described. For the reaction performed in batch conditions, for example, the monophasic approach is not able to reproduce the different plateau obtained by using different amount of catalyst or the induction time observed at low stirring rates. Moreover, it has been observed by operating in continuous reactors that micromixing has a dramatic effect on the reaction rate. At this purpose, we have recently observed that is possible to obtain a complete conversion to biodiesel in less than 10 seconds of reaction time. This observation is confirmed also by other authors using different types of reactors like: static mixers, micro-reactors, oscillatory flow reactors, cavitational reactors, microwave reactors or centrifugal contactors. In this work we will show that a recently proposed biphasic kinetic approach is able to describe all the aspects before mentioned that cannot be described by the monophasic kinetic model. In particular, we will show that the biphasic kinetic model can describe both the induction time observed in the batch reactors, at low stirring rate, and the very high conversions obtainable in a micro-channel reactor. The adopted biphasic kinetic model is based on a reliable reaction mechanism that will be validated by the experimental evidences reported in this work. (orig.)

  18. The biphasic response of rat vesical smooth muscle to ATP.

    OpenAIRE

    Bolego, C; Pinna, C.; Abbracchio, M. P.; Cattabeni, F.; Puglisi, L.

    1995-01-01

    1. Adenosine-5'-triphosphate (ATP) is known to exert a variety of biological effects via the activation of either ionotropic P2x- or G-protein coupled P2Y-purinoceptor subtypes. In this study the effects induced by ATP and ATP analogues on rat bladder strips were characterized at resting tone and in carbachol-prestimulated tissues. 2. ATP exerted a clear concentration-dependent biphasic response, which was maximal at 1 mM concentration and was characterized by an immediate and transient contr...

  19. Experimental demonstration of a second-order memristor and its ability to biorealistically implement synaptic plasticity.

    Science.gov (United States)

    Kim, Sungho; Du, Chao; Sheridan, Patrick; Ma, Wen; Choi, ShinHyun; Lu, Wei D

    2015-03-11

    Memristors have been extensively studied for data storage and low-power computation applications. In this study, we show that memristors offer more than simple resistance change. Specifically, the dynamic evolutions of internal state variables allow an oxide-based memristor to exhibit Ca(2+)-like dynamics that natively encode timing information and regulate synaptic weights. Such a device can be modeled as a second-order memristor and allow the implementation of critical synaptic functions realistically using simple spike forms based solely on spike activity. PMID:25710872

  20. DREAM (downstream regulatory element antagonist modulator) contributes to synaptic depression and contextual fear memory.

    Science.gov (United States)

    Wu, Long-Jun; Mellström, Britt; Wang, Hansen; Ren, Ming; Domingo, Sofia; Kim, Susan S; Li, Xiang-Yao; Chen, Tao; Naranjo, Jose R; Zhuo, Min

    2010-01-01

    The downstream regulatory element antagonist modulator (DREAM), a multifunctional Ca2+-binding protein, binds specifically to DNA and several nucleoproteins regulating gene expression and with proteins outside the nucleus to regulate membrane excitability or calcium homeostasis. DREAM is highly expressed in the central nervous system including the hippocampus and cortex; however, the roles of DREAM in hippocampal synaptic transmission and plasticity have not been investigated. Taking advantage of transgenic mice overexpressing a Ca2+-insensitive DREAM mutant (TgDREAM), we used integrative methods including electrophysiology, biochemistry, immunostaining, and behavior tests to study the function of DREAM in synaptic transmission, long-term plasticity and fear memory in hippocampal CA1 region. We found that NMDA receptor but not AMPA receptor-mediated current was decreased in TgDREAM mice. Moreover, synaptic plasticity, such as long-term depression (LTD) but not long-term potentiation (LTP), was impaired in TgDREAM mice. Biochemical experiments found that DREAM interacts with PSD-95 and may inhibit NMDA receptor function through this interaction. Contextual fear memory was significantly impaired in TgDREAM mice. By contrast, sensory responses to noxious stimuli were not affected. Our results demonstrate that DREAM plays a novel role in postsynaptic modulation of the NMDA receptor, and contributes to synaptic plasticity and behavioral memory. PMID:20205763

  1. DREAM (Downstream Regulatory Element Antagonist Modulator contributes to synaptic depression and contextual fear memory

    Directory of Open Access Journals (Sweden)

    Wu Long-Jun

    2010-01-01

    Full Text Available Abstract The downstream regulatory element antagonist modulator (DREAM, a multifunctional Ca2+-binding protein, binds specifically to DNA and several nucleoproteins regulating gene expression and with proteins outside the nucleus to regulate membrane excitability or calcium homeostasis. DREAM is highly expressed in the central nervous system including the hippocampus and cortex; however, the roles of DREAM in hippocampal synaptic transmission and plasticity have not been investigated. Taking advantage of transgenic mice overexpressing a Ca2+-insensitive DREAM mutant (TgDREAM, we used integrative methods including electrophysiology, biochemistry, immunostaining, and behavior tests to study the function of DREAM in synaptic transmission, long-term plasticity and fear memory in hippocampal CA1 region. We found that NMDA receptor but not AMPA receptor-mediated current was decreased in TgDREAM mice. Moreover, synaptic plasticity, such as long-term depression (LTD but not long-term potentiation (LTP, was impaired in TgDREAM mice. Biochemical experiments found that DREAM interacts with PSD-95 and may inhibit NMDA receptor function through this interaction. Contextual fear memory was significantly impaired in TgDREAM mice. By contrast, sensory responses to noxious stimuli were not affected. Our results demonstrate that DREAM plays a novel role in postsynaptic modulation of the NMDA receptor, and contributes to synaptic plasticity and behavioral memory.

  2. Imaging Exocytosis of Single Synaptic Vesicles at a Fast CNS Presynaptic Terminal.

    Science.gov (United States)

    Midorikawa, Mitsuharu; Sakaba, Takeshi

    2015-11-01

    Synaptic vesicles are tethered to the active zone where they are docked/primed so that they can fuse rapidly upon Ca(2+) influx. To directly study these steps at a CNS presynaptic terminal, we used total internal reflection fluorescence (TIRF) microscopy at the live isolated calyx of Held terminal and measured the movements of single synaptic vesicle just beneath the plasma membrane. Only a subset of vesicles within the TIRF field underwent exocytosis. Following exocytosis, new vesicles (newcomers) approached the membrane and refilled the release sites slowly with a time constant of several seconds. Uniform elevation of the intracellular Ca(2+) using flash photolysis elicited an exocytotic burst followed by the sustained component, representing release of the readily releasable vesicles and vesicle replenishment, respectively. Surprisingly, newcomers were not released within a second of high Ca(2+). Instead, already-tethered vesicles became release-ready and mediated the replenishment. Our results reveal an important feature of conventional synapses. PMID:26539890

  3. Imaging Exocytosis of Single Synaptic Vesicles at a Fast CNS Presynaptic Terminal.

    Science.gov (United States)

    Midorikawa, Mitsuharu; Sakaba, Takeshi

    2015-11-01

    Synaptic vesicles are tethered to the active zone where they are docked/primed so that they can fuse rapidly upon Ca(2+) influx. To directly study these steps at a CNS presynaptic terminal, we used total internal reflection fluorescence (TIRF) microscopy at the live isolated calyx of Held terminal and measured the movements of single synaptic vesicle just beneath the plasma membrane. Only a subset of vesicles within the TIRF field underwent exocytosis. Following exocytosis, new vesicles (newcomers) approached the membrane and refilled the release sites slowly with a time constant of several seconds. Uniform elevation of the intracellular Ca(2+) using flash photolysis elicited an exocytotic burst followed by the sustained component, representing release of the readily releasable vesicles and vesicle replenishment, respectively. Surprisingly, newcomers were not released within a second of high Ca(2+). Instead, already-tethered vesicles became release-ready and mediated the replenishment. Our results reveal an important feature of conventional synapses.

  4. Biphasic Chromatin Structure and FISH Signals Reflect Intranuclear Order

    Directory of Open Access Journals (Sweden)

    Jyoti P. Chaudhuri

    2005-01-01

    Full Text Available Background and Aim: One of the two parental allelic genes may selectively be expressed, regulated by imprinting, X-inactivation or by other less known mechanisms. This study aims to reflect on such genetic mechanisms. Materials and Methods: Slides from short term cultures or direct smears of blood, bone marrow and amniotic fluids were hybridized with FISH probes singly, combined or sequentially. Two to three hundred cells were examined from each preparation. Results and Aignificance: A small number of cells (up to about 5%, more frequent in leukemia cases, showed the twin features: (1 nuclei with biphasic chromatin, one part decondensed and the other condensed; and (2 homologous FISH signals distributed equitably in those two regions. The biphasic chromatin structure with equitable distribution of the homologous FISH signals may correspond to the two sets of chromosomes, supporting observations on ploidywise intranuclear order. The decondensed chromatin may relate to enhanced transcriptions or advanced replications. Conclusions: Transcriptions of only one of the two parental genomes cause allelic exclusion. Genomes may switch with alternating monoallelic expression of biallelic genes as an efficient genetic mechanism. If genomes fail to switch, allelic exclusion may lead to malignancy. Similarly, a genome-wide monoallelic replication may tilt the balance of heterozygosity resulting in aneusomy, initiating early events in malignant transformation and in predicting cancer mortality.

  5. Facile catalyst separation without water: Fluorous biphase hydroformylation of olefins

    Energy Technology Data Exchange (ETDEWEB)

    Horvath, I.T.; Rabai, J. [Exxon Research and Engineering Co., Annandale, NJ (United States)

    1994-10-07

    A novel concept for performing stoichiometric and catalytic chemical transformations has been developed that is based on the limited miscibility of partially or fully fluorinated compounds with nonfluorinated compounds. A fluorous biphase system (FBS) consists of a fluorous phase containing a dissolved reagent or catalyst and another phase, which could be any common organic or nonorganic solvent with limited or no solubility in the fluorous phase. The fluorous phase is defined as the fluorocarbon (mostly perfluorinated alkanes, ethers, and tertiary amines)-rich phase of a biphase system. An FBS compatible reagent or catalyst contains enough fluorous moieties that it will be soluble only or preferentially in the fluorous phase. The most effective fluorous moieties are linear or branched perfuoralkyl chains with high carbon number; they may also contain heteroatoms. The chemical transformation may occur either in the fluorous phase or at the interface of the two phases. The application of FBS has been demonstrated for the extraction of rhodium from toluene and for the hydroformylation of olefins. The ability to separate a catalyst or a reagent from the products completely at mild conditions could lead to industrial application of homogeneous catalysts or reagents and to the development of more environmentally benign processes.

  6. Cell-material interactions on biphasic polyurethane matrix.

    Science.gov (United States)

    Dicesare, Patrick; Fox, Wade M; Hill, Michael J; Krishnan, G Rajesh; Yang, Shuying; Sarkar, Debanjan

    2013-08-01

    Cell-matrix interaction is a key regulator for controlling stem cell fate in regenerative tissue engineering. These interactions are induced and controlled by the nanoscale features of extracellular matrix and are mimicked on synthetic matrices to control cell structure and functions. Recent studies have shown that nanostructured matrices can modulate stem cell behavior and exert specific role in tissue regeneration. In this study, we have demonstrated that nanostructured phase morphology of synthetic matrix can control adhesion, proliferation, organization and migration of human mesenchymal stem cells (MSCs). Nanostructured biodegradable polyurethanes (PU) with segmental composition exhibit biphasic morphology at nanoscale dimensions and can control cellular features of MSCs. Biodegradable PU with polyester soft segment and hard segment composed of aliphatic diisocyanates and dipeptide chain extender were designed to examine the effect polyurethane phase morphology. By altering the polyurethane composition, morphological architecture of PU was modulated and its effect was examined on MSC. Results show that MSCs can sense the nanoscale morphology of biphasic polyurethane matrix to exhibit distinct cellular features and, thus, signifies the relevance of matrix phase morphology. The role of nanostructured phases of a synthetic matrix in controlling cell-matrix interaction provides important insights for regulation of cell behavior on synthetic matrix and, therefore, is an important tool for engineering tissue regeneration. PMID:23255285

  7. Programmable synaptic chip for electronic neural networks

    Science.gov (United States)

    Moopenn, A.; Langenbacher, H.; Thakoor, A. P.; Khanna, S. K.

    1988-01-01

    A binary synaptic matrix chip has been developed for electronic neural networks. The matrix chip contains a programmable 32X32 array of 'long channel' NMOSFET binary connection elements implemented in a 3-micron bulk CMOS process. Since the neurons are kept off-chip, the synaptic chip serves as a 'cascadable' building block for a multi-chip synaptic network as large as 512X512 in size. As an alternative to the programmable NMOSFET (long channel) connection elements, tailored thin film resistors are deposited, in series with FET switches, on some CMOS test chips, to obtain the weak synaptic connections. Although deposition and patterning of the resistors require additional processing steps, they promise substantial savings in silicon area. The performance of synaptic chip in a 32-neuron breadboard system in an associative memory test application is discussed.

  8. Learning and reconsolidation implicate different synaptic mechanisms.

    Science.gov (United States)

    Li, Yan; Meloni, Edward G; Carlezon, William A; Milad, Mohammed R; Pitman, Roger K; Nader, Karim; Bolshakov, Vadim Y

    2013-03-19

    Synaptic mechanisms underlying memory reconsolidation after retrieval are largely unknown. Here we report that synapses in projections to the lateral nucleus of the amygdala implicated in auditory fear conditioning, which are potentiated by learning, enter a labile state after memory reactivation, and must be restabilized through a postsynaptic mechanism implicating the mammalian target of rapamycin kinase-dependent signaling. Fear-conditioning-induced synaptic enhancements were primarily presynaptic in origin. Reconsolidation blockade with rapamycin, inhibiting mammalian target of rapamycin kinase activity, suppressed synaptic potentiation in slices from fear-conditioned rats. Surprisingly, this reduction of synaptic efficacy was mediated by post- but not presynaptic mechanisms. These findings suggest that different plasticity rules may apply to the processes underlying the acquisition of original fear memory and postreactivational stabilization of fear-conditioning-induced synaptic enhancements mediating fear memory reconsolidation. PMID:23487762

  9. Synaptic vesicle proteins and active zone plasticity

    Directory of Open Access Journals (Sweden)

    Robert J Kittel

    2016-04-01

    Full Text Available Neurotransmitter is released from synaptic vesicles at the highly specialized presynaptic active zone. The complex molecular architecture of active zones mediates the speed, precision and plasticity of synaptic transmission. Importantly, structural and functional properties of active zones vary significantly, even for a given connection. Thus, there appear to be distinct active zone states, which fundamentally influence neuronal communication by controlling the positioning and release of synaptic vesicles. Vice versa, recent evidence has revealed that synaptic vesicle components also modulate organizational states of the active zone.The protein-rich cytomatrix at the active zone (CAZ provides a structural platform for molecular interactions guiding vesicle exocytosis. Studies in Drosophila have now demonstrated that the vesicle proteins Synaptotagmin-1 (Syt1 and Rab3 also regulate glutamate release by shaping differentiation of the CAZ ultrastructure. We review these unexpected findings and discuss mechanistic interpretations of the reciprocal relationship between synaptic vesicles and active zone states, which has heretofore received little attention.

  10. Synaptic Vesicle Proteins and Active Zone Plasticity.

    Science.gov (United States)

    Kittel, Robert J; Heckmann, Manfred

    2016-01-01

    Neurotransmitter is released from synaptic vesicles at the highly specialized presynaptic active zone (AZ). The complex molecular architecture of AZs mediates the speed, precision and plasticity of synaptic transmission. Importantly, structural and functional properties of AZs vary significantly, even for a given connection. Thus, there appear to be distinct AZ states, which fundamentally influence neuronal communication by controlling the positioning and release of synaptic vesicles. Vice versa, recent evidence has revealed that synaptic vesicle components also modulate organizational states of the AZ. The protein-rich cytomatrix at the active zone (CAZ) provides a structural platform for molecular interactions guiding vesicle exocytosis. Studies in Drosophila have now demonstrated that the vesicle proteins Synaptotagmin-1 (Syt1) and Rab3 also regulate glutamate release by shaping differentiation of the CAZ ultrastructure. We review these unexpected findings and discuss mechanistic interpretations of the reciprocal relationship between synaptic vesicles and AZ states, which has heretofore received little attention.

  11. Estrous Cycle-Dependent Phasic Changes in the Stoichiometry of Hippocampal Synaptic AMPA Receptors in Rats

    OpenAIRE

    Hirobumi Tada; Mayu Koide; Wakana Ara; Yusuke Shibata; Toshiya Funabashi; Kumiko Suyama; Takahisa Goto; Takuya Takahashi

    2015-01-01

    Cognitive function can be affected by the estrous cycle. However, the effect of the estrous cycle on synaptic functions is poorly understood. Here we show that in female rats, inhibitory-avoidance (IA) task (hippocampus-dependent contextual fear-learning task) drives GluA2-lacking Ca2+-permeable AMPA receptors (CP-AMPARs) into the hippocampal CA3-CA1 synapses during all periods of the estrous cycle except the proestrous period, when estrogen levels are high. In addition, IA task failed to dri...

  12. Generic Model-Based Tailor-Made Design and Analysis of Biphasic Reaction Systems

    DEFF Research Database (Denmark)

    Anantpinijwatna, Amata

    systems have a broad range of application, such as the manufacture of petroleum based chemicals, pharmaceuticals, and agro-bio products. Major considerations in the design and analysis of biphasic reaction systems are physical and chemical equilibria, kinetic mechanisms, and reaction rates. The primary......Biphasic reaction systems are composed of immiscible aqueous and organic liquid phases where reactants, products, and catalysts are partitioned. These biphasic conditions point to novel synthesis paths, higher yields, and faster reactions, as well as facilitate product separation. The biphasic...... contribution of this thesis is the development of a systematic modelling framework for the biphasic reaction system. The developed framework consists of three modules describing phase equilibria, reactions and mass transfer, and material balances of such processes. Correlative and predictive thermodynamic...

  13. A sequential vesicle pool model with a single release sensor and a ca(2+)-dependent priming catalyst effectively explains ca(2+)-dependent properties of neurosecretion

    DEFF Research Database (Denmark)

    Walter, Alexander M; da Silva Pinheiro, Paulo César; Verhage, Matthijs;

    2013-01-01

    predictions to data from mouse chromaffin cells. Like the PPM, the SPM explains biphasic release, Ca(2+)-dependence and pool sizes in mouse chromaffin cells. In addition, the SPM accounts for the rapid recovery of the fast component after strong stimulation, where the PPM fails. The SPM also predicts...

  14. Generation and behavior characterization of CaMKIIβ knockout mice.

    Directory of Open Access Journals (Sweden)

    Adam D Bachstetter

    Full Text Available The calcium/calmodulin-dependent protein kinase II (CaMKII is abundant in the brain, where it makes important contributions to synaptic organization and homeostasis, including playing an essential role in synaptic plasticity and memory. Four genes encode isoforms of CaMKII (α, β, δ, γ, with CaMKIIα and CaMKIIβ highly expressed in the brain. Decades of molecular and cellular research, as well as the use of a large number of CaMKIIα mutant mouse lines, have provided insight into the pivotal roles of CaMKIIα in brain plasticity and cognition. However, less is known about the CaMKIIβ isoform. We report the development and extensive behavioral and phenotypic characterization of a CaMKIIβ knockout (KO mouse. The CaMKIIβ KO mouse was found to be smaller at weaning, with an altered body mass composition. The CaMKIIβ KO mouse showed ataxia, impaired forelimb grip strength, and deficits in the rotorod, balance beam and running wheel tasks. Interestingly, the CaMKIIβ KO mouse exhibited reduced anxiety in the elevated plus maze and open field tests. The CaMKIIβ KO mouse also showed cognitive impairment in the novel object recognition task. Our results provide a comprehensive behavioral characterization of mice deficient in the β isoform of CaMKII. The neurologic phenotypes and the construction of the genotype suggest the utility of this KO mouse strain for future studies of CaMKIIβ in brain structure, function and development.

  15. Influence of saline solution on hydration behavior of β-dicalcium silicate in comparison with biphasic calcium phosphate/hydroxyapatite bio-ceramics.

    Science.gov (United States)

    Radwan, M M; Abd El-Hamid, H K; Mohamed, A F

    2015-12-01

    The influence of using saline solution as mixing and curing liquid on some characteristics of β-dicalcium silicate (β-C2S) and biphasic compound tri-calcium phosphate/hydroxyapatite (TCP/HAp) bio-ceramics was investigated. β-C2S (27-30 nm) was prepared by solid state reaction at 1450°C, while biphasic compound TCP/HAp (7-15 nm) was synthesized from an aqueous solution of Ca(NO3)2·4H2O and (NH4)2HPO4·12H2O by chemical precipitation method. Setting times, compressive strength, pH values, X-ray diffraction analysis, infrared spectroscopy, scanning electron microscopy (SEM) were investigated. The evaluation of cytotoxicity of both calcium silicate and biphasic compounds to human gingival fibroblasts was carried out. The use of saline solution as mixing and immersing liquid shortened the setting time for the two bio-cements. TCP/HAp did not show any mechanical strength but β-C2S showed good strength values. Both synthesized compounds showed a moderate cytotoxicity and both materials were effective in a no significant way.

  16. Oscillatory Motion of a Bi-Phasic Slug in a Teflon Reactor

    Science.gov (United States)

    Abolhasani, Milad; Jensen, Klavs

    2015-11-01

    Bi-phasic physical/chemical processes require transfer of solute/reagent molecules across the interface. Continuous multi-phase flow approaches (using gas as the continuous phase), usually fail in providing sufficient interfacial area for transfer of molecules between the aqueous and organic phases. In continuous segmented flow platforms (with a fluorinated polymer-based reactor), the higher surface tension of the aqueous phase compared to the organic phase of a bi-phasic slug, in combination with the low surface energy of the reactor wall result in a more facile motion of the aqueous phase. Thus, upon applying a pressure gradient across the bi-phasic slug, the aqueous phase of the slug moves through the organic phase and leads the bi-phasic slug, thereby limiting the available interfacial area for the bi-phasic mass transfer only to the semi-spherical interface between the two phases. Disrupting the quasi-equilibrium state of the bi-phasic slug through reversing the pressure gradient across the bi-phasic slug causes the aqueous phase to move back through the organic phase. In this work, we experimentally investigate the dynamics of periodic alteration of the pressure gradient across a bi-phasic slug, and characterize the resulting enhanced interfacial area on the bi-phasic mass transfer rate. We demonstrate the enhanced mass transfer rate of the oscillatory flow strategy compared to the continuous multi-phase approach using bi-phasic Pd catalyzed carbon-carbon and carbon-nitrogen cross coupling reactions. NSERC Postdoctoral Fellowship, Novartis Center for Continuous Manufacturing.

  17. Schisandra N-butanol extract improves synaptic morphology and plasticity in ovarectomized mice

    Institute of Scientific and Technical Information of China (English)

    Meiyan Yang; Zhaolin Cai; Peng Xiao; Chuhua Li

    2012-01-01

    Preliminary work by our research team revealed that Schisandra, a renowned traditional Chinese medicine, causes learning and memory improvements in ovariectomized mice. This activity was attributed to active ingredients extracted with N-butyl alcohol, named Schisandra N-butanol extract. In this study, ovariectomized mice were pretreated with Schisandra N-butanol extract given by intragastric administration. This treatment led to the enhancement of learning, and an increase in hippocampal CA1 synaptic, surface and postsynaptic density. A decrease in the average size of the synaptic active zone was also observed. These experimental findings showing that Schisandra N-butanol extract improved synaptic morphology indicate an underlying mechanism by which the ability of learning is enhanced in ovariectomized mice.

  18. Neuromodulation of the Feedforward Dentate Gyrus-CA3 Microcircuit

    Science.gov (United States)

    Prince, Luke Y.; Bacon, Travis J.; Tigaret, Cezar M.; Mellor, Jack R.

    2016-01-01

    The feedforward dentate gyrus-CA3 microcircuit in the hippocampus is thought to activate ensembles of CA3 pyramidal cells and interneurons to encode and retrieve episodic memories. The creation of these CA3 ensembles depends on neuromodulatory input and synaptic plasticity within this microcircuit. Here we review the mechanisms by which the neuromodulators aceylcholine, noradrenaline, dopamine, and serotonin reconfigure this microcircuit and thereby infer the net effect of these modulators on the processes of episodic memory encoding and retrieval. PMID:27799909

  19. Distance-dependent homeostatic synaptic scaling mediated by A-type potassium channels

    Directory of Open Access Journals (Sweden)

    Hiroshi T Ito

    2009-11-01

    Full Text Available Many lines of evidence suggest that the efficacy of synapses on CA1 pyramidal neuron dendrites increases as a function of distance from the cell body. The strength of an individual synapse is also dynamically modulated by activity-dependent synaptic plasticity, which raises the question as to how a neuron can reconcile individual synaptic changes with the maintenance of the proximal-to-distal gradient of synaptic strength along the dendrites. As the density of A-type potassium channels exhibits a similar gradient from proximal (low-to-distal (high dendrites, the A-current may play a role in coordinating local synaptic changes with the global synaptic strength gradient. Here we describe a form of homeostatic plasticity elicited by conventional activity blockade (with TTX coupled with a block of the A-type potassium channel. Following A-type potassium channel inhibition for 12 hrs, recordings from CA1 somata revealed a significantly higher miniature excitatory postsynaptic current (mEPSC frequency, whereas in dendritic recordings, there was no change in mEPSC frequency. Consistent with mEPSC recordings, we observed a significant increase in AMPA receptor density in stratum pyramidale but not stratum radiatum. Based on these data, we propose that the differential distribution of A-type potassium channels along the apical dendrites may create a proximal-to-distal membrane potential gradient. This gradient may regulate AMPA receptor distribution along the same axis. Taken together, our results indicate that A-type potassium channels play an important role in controlling synaptic strength along the dendrites, which may help to maintain the computational capacity of the neuron.

  20. The requirement of BDNF for hippocampal synaptic plasticity is experience‐dependent

    Science.gov (United States)

    Aarse, Janna; Herlitze, Stefan

    2016-01-01

    ABSTRACT Brain‐derived neurotrophic factor (BDNF) supports neuronal survival, growth, and differentiation and has been implicated in forms of hippocampus‐dependent learning. In vitro, a specific role in hippocampal synaptic plasticity has been described, although not all experience‐dependent forms of synaptic plasticity critically depend on BDNF. Synaptic plasticity is likely to enable long‐term synaptic information storage and memory, and the induction of persistent (>24 h) forms, such as long‐term potentiation (LTP) and long‐term depression (LTD) is tightly associated with learning specific aspects of a spatial representation. Whether BDNF is required for persistent (>24 h) forms of LTP and LTD, and how it contributes to synaptic plasticity in the freely behaving rodent has never been explored. We examined LTP, LTD, and related forms of learning in the CA1 region of freely dependent mice that have a partial knockdown of BDNF (BDNF+/−). We show that whereas early‐LTD (BDNF, short‐term depression (BDNF is required for LTP that is induced by mild, but not strong short afferent stimulation protocols. Object‐place learning triggers LTD in the CA1 region of mice. We observed that object‐place memory was impaired and the object‐place exploration failed to induce LTD in BDNF+/− mice. Furthermore, spatial reference memory, that is believed to be enabled by LTP, was also impaired. Taken together, these data indicate that BDNF is required for specific, but not all, forms of hippocampal‐dependent information storage and memory. Thus, very robust forms of synaptic plasticity may circumvent the need for BDNF, rather it may play a specific role in the optimization of weaker forms of plasticity. The finding that both learning‐facilitated LTD and spatial reference memory are both impaired in BDNF+/− mice, suggests moreover, that it is critically required for the physiological encoding of hippocampus‐dependent memory. © 2015 The Authors

  1. Bassoon specifically controls presynaptic P/Q-type Ca(2+) channels via RIM-binding protein.

    Science.gov (United States)

    Davydova, Daria; Marini, Claudia; King, Claire; Klueva, Julia; Bischof, Ferdinand; Romorini, Stefano; Montenegro-Venegas, Carolina; Heine, Martin; Schneider, Romy; Schröder, Markus S; Altrock, Wilko D; Henneberger, Christian; Rusakov, Dmitri A; Gundelfinger, Eckart D; Fejtova, Anna

    2014-04-01

    Voltage-dependent Ca(2+) channels (CaVs) represent the principal source of Ca(2+) ions that trigger evoked neurotransmitter release from presynaptic boutons. Ca(2+) influx is mediated mainly via CaV2.1 (P/Q-type) and CaV2.2 (N-type) channels, which differ in their properties. Their relative contribution to synaptic transmission changes during development and tunes neurotransmission during synaptic plasticity. The mechanism of differential recruitment of CaV2.1 and CaV2.2 to release sites is largely unknown. Here, we show that the presynaptic scaffolding protein Bassoon localizes specifically CaV2.1 to active zones via molecular interaction with the RIM-binding proteins (RBPs). A genetic deletion of Bassoon or an acute interference with Bassoon-RBP interaction reduces synaptic abundance of CaV2.1, weakens P/Q-type Ca(2+) current-driven synaptic transmission, and results in higher relative contribution of neurotransmission dependent on CaV2.2. These data establish Bassoon as a major regulator of the molecular composition of the presynaptic neurotransmitter release sites. PMID:24698275

  2. Estrous Cycle-Dependent Phasic Changes in the Stoichiometry of Hippocampal Synaptic AMPA Receptors in Rats.

    Directory of Open Access Journals (Sweden)

    Hirobumi Tada

    Full Text Available Cognitive function can be affected by the estrous cycle. However, the effect of the estrous cycle on synaptic functions is poorly understood. Here we show that in female rats, inhibitory-avoidance (IA task (hippocampus-dependent contextual fear-learning task drives GluA2-lacking Ca2+-permeable AMPA receptors (CP-AMPARs into the hippocampal CA3-CA1 synapses during all periods of the estrous cycle except the proestrous period, when estrogen levels are high. In addition, IA task failed to drive CP-AMPARs into the CA3-CA1 synapses of ovariectomized rats only when estrogen was present. Thus, changes in the stoichiometry of AMPA receptors during learning depend on estrogen levels. Furthermore, the induction of long-term potentiation (LTP after IA task was prevented during the proestrous period, while intact LTP is still expressed after IA task during other period of the estrous cycle. Consistent with this finding, rats conditioned by IA training failed to acquire hippocampus-dependent Y-maze task during the proestrous period. On the other hand, during other estrous period, rats were able to learn Y-maze task after IA conditioning. These results suggest that high estrogen levels prevent the IA learning-induced delivery of CP-AMPARs into hippocampal CA3-CA1 synapses and limit synaptic plasticity after IA task, thus preventing the acquisition of additional learning.

  3. Estrous Cycle-Dependent Phasic Changes in the Stoichiometry of Hippocampal Synaptic AMPA Receptors in Rats.

    Science.gov (United States)

    Tada, Hirobumi; Koide, Mayu; Ara, Wakana; Shibata, Yusuke; Funabashi, Toshiya; Suyama, Kumiko; Goto, Takahisa; Takahashi, Takuya

    2015-01-01

    Cognitive function can be affected by the estrous cycle. However, the effect of the estrous cycle on synaptic functions is poorly understood. Here we show that in female rats, inhibitory-avoidance (IA) task (hippocampus-dependent contextual fear-learning task) drives GluA2-lacking Ca2+-permeable AMPA receptors (CP-AMPARs) into the hippocampal CA3-CA1 synapses during all periods of the estrous cycle except the proestrous period, when estrogen levels are high. In addition, IA task failed to drive CP-AMPARs into the CA3-CA1 synapses of ovariectomized rats only when estrogen was present. Thus, changes in the stoichiometry of AMPA receptors during learning depend on estrogen levels. Furthermore, the induction of long-term potentiation (LTP) after IA task was prevented during the proestrous period, while intact LTP is still expressed after IA task during other period of the estrous cycle. Consistent with this finding, rats conditioned by IA training failed to acquire hippocampus-dependent Y-maze task during the proestrous period. On the other hand, during other estrous period, rats were able to learn Y-maze task after IA conditioning. These results suggest that high estrogen levels prevent the IA learning-induced delivery of CP-AMPARs into hippocampal CA3-CA1 synapses and limit synaptic plasticity after IA task, thus preventing the acquisition of additional learning. PMID:26121335

  4. Control of Ca2+ Influx and Calmodulin Activation by SK-Channels in Dendritic Spines.

    Directory of Open Access Journals (Sweden)

    Thom Griffith

    2016-05-01

    Full Text Available The key trigger for Hebbian synaptic plasticity is influx of Ca2+ into postsynaptic dendritic spines. The magnitude of [Ca2+] increase caused by NMDA-receptor (NMDAR and voltage-gated Ca2+ -channel (VGCC activation is thought to determine both the amplitude and direction of synaptic plasticity by differential activation of Ca2+ -sensitive enzymes such as calmodulin. Ca2+ influx is negatively regulated by Ca2+ -activated K+ channels (SK-channels which are in turn inhibited by neuromodulators such as acetylcholine. However, the precise mechanisms by which SK-channels control the induction of synaptic plasticity remain unclear. Using a 3-dimensional model of Ca2+ and calmodulin dynamics within an idealised, but biophysically-plausible, dendritic spine, we show that SK-channels regulate calmodulin activation specifically during neuron-firing patterns associated with induction of spike timing-dependent plasticity. SK-channel activation and the subsequent reduction in Ca2+ influx through NMDARs and L-type VGCCs results in an order of magnitude decrease in calmodulin (CaM activation, providing a mechanism for the effective gating of synaptic plasticity induction. This provides a common mechanism for the regulation of synaptic plasticity by neuromodulators.

  5. Synaptic network activity induces neuronal differentiation of adult hippocampal precursor cells through BDNF signaling

    Directory of Open Access Journals (Sweden)

    Harish Babu

    2009-09-01

    Full Text Available Adult hippocampal neurogenesis is regulated by activity. But how do neural precursor cells in the hippocampus respond to surrounding network activity and translate increased neural activity into a developmental program? Here we show that long-term potential (LTP-like synaptic activity within a cellular network of mature hippocampal neurons promotes neuronal differentiation of newly generated cells. In co-cultures of precursor cells with primary hippocampal neurons, LTP-like synaptic plasticity induced by addition of glycine in Mg2+-free media for 5 min, produced synchronous network activity and subsequently increased synaptic strength between neurons. Furthermore, this synchronous network activity led to a significant increase in neuronal differentiation from the co-cultured neural precursor cells. When applied directly to precursor cells, glycine and Mg2+-free solution did not induce neuronal differentiation. Synaptic plasticity-induced neuronal differentiation of precursor cells was observed in the presence of GABAergic neurotransmission blockers but was dependent on NMDA-mediated Ca2+ influx. Most importantly, neuronal differentiation required the release of brain-derived neurotrophic factor (BDNF from the underlying substrate hippocampal neurons as well as TrkB receptor phosphorylation in precursor cells. This suggests that activity-dependent stem cell differentiation within the hippocampal network is mediated via synaptically evoked BDNF signaling.

  6. Age dependence of the rapid antidepressant and synaptic effects of acute NMDA receptor blockade

    Directory of Open Access Journals (Sweden)

    Elena eNosyreva

    2014-12-01

    Full Text Available Ketamine is a NMDA receptor antagonist that produces rapid antidepressant responses in individuals with major depressive disorder. The antidepressant action of ketamine has been linked to blocking NMDA receptor activation at rest, which inhibits eukaryotic elongation factor2 kinase leading to desuppression of protein synthesis and synaptic potentiation in the CA1 region of the hippocampus. Here, we investigated ketamine mediated antidepressant response and the resulting synaptic potentiation in juvenile animals. We found that ketamine did not produce an antidepressant response in juvenile animals in the novelty suppressed feeding or the forced swim test. In addition ketamine application failed to trigger synaptic potentiation in hippocampal slices obtained from juvenile animals, unlike its action in slices from older animals (6-9 weeks old. The inability of ketamine to trigger an antidepressant response or subsequent synaptic plasticity processes suggests a developmental component to ketamine mediated antidepressant efficacy. We also show that the NMDAR antagonist AP5 triggers synaptic potentiation in mature hippocampus similar to the action of ketamine, demonstrating that global competitive blockade of NMDA receptors is sufficient to trigger this effect. These findings suggest that global blockade of NMDA receptors in developmentally mature hippocampal synapses are required for the antidepressant efficacy of ketamine.

  7. Plasticity of inhibitory synaptic network interactions in the lateral amygdala upon fear conditioning in mice.

    Science.gov (United States)

    Szinyei, Csaba; Narayanan, Rajeevan T; Pape, Hans-Christian

    2007-02-01

    After fear conditioning, plastic changes of excitatory synaptic transmission occur in the amygdala. Fear-related memory also involves the GABAergic system, although no influence on inhibitory synaptic transmission is known. In the present study we assessed the influence of Pavlovian fear conditioning on the plasticity of GABAergic synaptic interactions in the lateral amygdala (LA) in brain slices prepared from fear-conditioned, pseudo-trained and naïve adult mice. Theta-burst tetanization of thalamic afferent inputs to the LA evoked an input-specific potentiation of inhibitory postsynaptic responses in projection neurons; the cortical input was unaffected. Philanthotoxin (10 microM), an antagonist of Ca2+-permeable AMPA receptors, disabled this plastic phenomenon. Surgical isolation of the LA, extracellular application of a GABA(B) receptor antagonist (CGP 55845A, 10 microM) or an NMDA receptor antagonist (APV, 50 microM), or intracellular application of BAPTA (10 mM), did not influence the plasticity. The plasticity also showed as a potentiation of monosynaptic excitatory responses in putative GABAergic interneurons. Pavlovian fear conditioning, but not pseudo-conditioning, resulted in a significant reduction in this potentiation that was evident 24 h after training. Two weeks after training, the potentiation returned to control levels. In conclusion, a reduction in potentiation of inhibitory synaptic interactions occurs in the LA and may contribute to a shift in synaptic balance towards excitatory signal flow during the processes of fear-memory acquisition or consolidation.

  8. ApoE isoform-dependent changes in hippocampal synaptic function

    Directory of Open Access Journals (Sweden)

    Sullivan Patrick M

    2009-05-01

    Full Text Available Abstract The lipoprotein receptor system in the hippocampus is intimately involved in the modulation of synaptic transmission and plasticity. The association of specific apoE isoform expression with human neurodegenerative disorders has focused attention on the role of these apoE isoforms in lipoprotein receptor-dependent synaptic modulation. In the present study, we used the apoE2, apoE3 and apoE4 targeted replacement (TR mice along with recombinant human apoE isoforms to determine the role of apoE isoforms in hippocampus area CA1 synaptic function. While synaptic transmission is unaffected by apoE isoform, long-term potentiation (LTP is significantly enhanced in apoE4 TR mice versus apoE2 TR mice. ApoE isoform-dependent differences in LTP induction require NMDA-receptor function, and apoE isoform expression alters activation of both ERK and JNK signal transduction. Acute application of specific apoE isoforms also alters LTP induction while decreasing NMDA-receptor mediated field potentials. Furthermore, acute apoE isoform application does not have the same effects on ERK and JNK activation. These findings demonstrate specific, isoform-dependent effects of human apoE isoforms on adult hippocampus synaptic plasticity and highlight mechanistic differences between chronic apoE isoform expression and acute apoE isoform exposure.

  9. Modelling bidirectional modulations in synaptic plasticity: A biochemical pathway model to understand the emergence of long term potentiation (LTP) and long term depression (LTD).

    Science.gov (United States)

    He, Yao; Kulasiri, Don; Samarasinghe, Sandhya

    2016-08-21

    Synaptic plasticity induces bidirectional modulations of the postsynaptic response following a synaptic transmission. The long term forms of synaptic plasticity, named long term potentiation (LTP) and long term depression (LTD), are critical for the antithetic functions of the memory system, memory formation and removal, respectively. A common Ca(2+) signalling upstream triggers both LTP and LTD, and the critical proteins and factors coordinating the LTP/LTD inductions are not well understood. We develop an integrated model based on the sub-models of the indispensable synaptic proteins in the emergence of synaptic plasticity to validate and understand their potential roles in the expression of synaptic plasticity. The model explains Ca(2+)/calmodulin (CaM) complex dependent coordination of LTP/LTD expressions by the interactions among the indispensable proteins using the experimentally estimated kinetic parameters. Analysis of the integrated model provides us with insights into the effective timescales of the key proteins and we conclude that the CaM pool size is critical for the coordination between LTP/LTD expressions. PMID:27185535

  10. The role of microglia in synaptic stripping and synaptic degeneration: a revised perspective

    OpenAIRE

    Perry, V. Hugh; O'Connor, Vincent

    2010-01-01

    Chronic neurodegenerative diseases of the CNS (central nervous system) are characterized by the loss of neurons. There is, however, growing evidence to show that an early stage of this process involves degeneration of presynaptic terminals prior to the loss of the cell body. Synaptic plasticity in CNS pathology has been associated with microglia and the phenomenon of synaptic stripping. We review here the evidence for the involvement of microglia in synaptic stripping and synapse degeneration...

  11. Dopamine Regulates Aversive Contextual Learning and Associated In Vivo Synaptic Plasticity in the Hippocampus

    Directory of Open Access Journals (Sweden)

    John I. Broussard

    2016-03-01

    Full Text Available Dopamine release during reward-driven behaviors influences synaptic plasticity. However, dopamine innervation and release in the hippocampus and its role during aversive behaviors are controversial. Here, we show that in vivo hippocampal synaptic plasticity in the CA3-CA1 circuit underlies contextual learning during inhibitory avoidance (IA training. Immunohistochemistry and molecular techniques verified sparse dopaminergic innervation of the hippocampus from the midbrain. The long-term synaptic potentiation (LTP underlying the learning of IA was assessed with a D1-like dopamine receptor agonist or antagonist in ex vivo hippocampal slices and in vivo in freely moving mice. Inhibition of D1-like dopamine receptors impaired memory of the IA task and prevented the training-induced enhancement of both ex vivo and in vivo LTP induction. The results indicate that dopamine-receptor signaling during an aversive contextual task regulates aversive memory retention and regulates associated synaptic mechanisms in the hippocampus that likely underlie learning.

  12. Astroglial calcium signaling displays short-term plasticity and adjusts synaptic efficacy

    Directory of Open Access Journals (Sweden)

    Jeremie eSibille

    2015-05-01

    Full Text Available Astrocytes are dynamic signaling brain elements able to sense neuronal inputs and to respond by complex calcium signals, which are thought to represent their excitability. Such signaling has been proposed to modulate, or not, neuronal activities ranging from basal synaptic transmission to epileptiform discharges. However, whether calcium signaling in astrocytes exhibits activity-dependent changes and acutely modulates short-term synaptic plasticity is currently unclear. We here show, using dual recordings of astroglial calcium signals and synaptic transmission, that calcium signaling in astrocytes displays, concomitantly to excitatory synapses, short-term plasticity in response to prolonged repetitive and tetanic stimulations of Schaffer collaterals. We also found that acute inhibition of calcium signaling in astrocytes by intracellular calcium chelation rapidly potentiates excitatory synaptic transmission and short-term plasticity of Shaffer collateral CA1 synapses, i.e. paired-pulse facilitation and responses to tetanic and prolonged repetitive stimulation. These data reveal that calcium signaling of astrocytes is plastic and down-regulates basal transmission and short-term plasticity of hippocampal CA1 glutamatergic synapses.

  13. Facilitation of AMPA receptor synaptic delivery as a molecular mechanism for cognitive enhancement.

    Directory of Open Access Journals (Sweden)

    Shira Knafo

    2012-02-01

    Full Text Available Cell adhesion molecules and downstream growth factor-dependent signaling are critical for brain development and synaptic plasticity, and they have been linked to cognitive function in adult animals. We have previously developed a mimetic peptide (FGL from the neural cell adhesion molecule (NCAM that enhances spatial learning and memory in rats. We have now investigated the cellular and molecular basis of this cognitive enhancement, using biochemical, morphological, electrophysiological, and behavioral analyses. We have found that FGL triggers a long-lasting enhancement of synaptic transmission in hippocampal CA1 neurons. This effect is mediated by a facilitated synaptic delivery of AMPA receptors, which is accompanied by enhanced NMDA receptor-dependent long-term potentiation (LTP. Both LTP and cognitive enhancement are mediated by an initial PKC activation, which is followed by persistent CaMKII activation. These results provide a mechanistic link between facilitation of AMPA receptor synaptic delivery and improved hippocampal-dependent learning, induced by a pharmacological cognitive enhancer.

  14. Lavandula angustifolia extract improves deteriorated synaptic plasticity in an animal model of Alzheimer’s disease

    Directory of Open Access Journals (Sweden)

    Masoud Soheili

    2015-11-01

    Full Text Available Objective(s:Neurodegenerative Alzheimer’s disease (AD is associated with profound deficits in synaptic transmission and synaptic plasticity. Long-term potentiation (LTP, an experimental form of synaptic plasticity, is intensively examined in hippocampus. In this study we evaluated the effect of aqueous extract of lavender (Lavandula angustifolia on induction of LTP in the CA1 area of hippocampus. In response to stimulation of the Schaffer collaterals the baseline or tetanized field extracellular postsynaptic potentials (fEPSPs were recorded in the CA1 area. Materials and Methods: The electrophysiological recordings were carried out in four groups of rats; two control groups including the vehicle (CON and lavender (CE treated rats and two Alzheimeric groups including the vehicle (ALZ and lavender (AE treated animals. Results: The extract inefficiently affected the baseline responses in the four testing groups. While the fEPSPs displayed a considerable LTP in the CON animals, no potentiation was evident in the tetanized responses in the ALZ rats. The herbal medicine effectively restored LTP in the AE group and further potentiated fEPSPs in the CE group. Conclusion:The positive effect of the lavender extract on the plasticity of synaptic transmission supports its previously reported behavioral effects on improvement of impaired spatial memory in the Alzheimeric animals.

  15. Programmable synaptic devices for electronic neural nets

    Science.gov (United States)

    Moopenn, A.; Thakoor, A. P.

    1990-01-01

    The architecture, design, and operational characteristics of custom VLSI and thin film synaptic devices are described. The devices include CMOS-based synaptic chips containing 1024 reprogrammable synapses with a 6-bit dynamic range, and nonvolatile, write-once, binary synaptic arrays based on memory switching in hydrogenated amorphous silicon films. Their suitability for embodiment of fully parallel and analog neural hardware is discussed. Specifically, a neural network solution to an assignment problem of combinatorial global optimization, implemented in fully parallel hardware using the synaptic chips, is described. The network's ability to provide optimal and near optimal solutions over a time scale of few neuron time constants has been demonstrated and suggests a speedup improvement of several orders of magnitude over conventional search methods.

  16. AMPA receptor inhibition by synaptically released zinc.

    Science.gov (United States)

    Kalappa, Bopanna I; Anderson, Charles T; Goldberg, Jacob M; Lippard, Stephen J; Tzounopoulos, Thanos

    2015-12-22

    The vast amount of fast excitatory neurotransmission in the mammalian central nervous system is mediated by AMPA-subtype glutamate receptors (AMPARs). As a result, AMPAR-mediated synaptic transmission is implicated in nearly all aspects of brain development, function, and plasticity. Despite the central role of AMPARs in neurobiology, the fine-tuning of synaptic AMPA responses by endogenous modulators remains poorly understood. Here we provide evidence that endogenous zinc, released by single presynaptic action potentials, inhibits synaptic AMPA currents in the dorsal cochlear nucleus (DCN) and hippocampus. Exposure to loud sound reduces presynaptic zinc levels in the DCN and abolishes zinc inhibition, implicating zinc in experience-dependent AMPAR synaptic plasticity. Our results establish zinc as an activity-dependent, endogenous modulator of AMPARs that tunes fast excitatory neurotransmission and plasticity in glutamatergic synapses.

  17. Brain circuitry outside the synaptic cleft

    OpenAIRE

    Rusakov, Dmitri A.; Alexander E Dityatev

    2014-01-01

    A growing body of experimental evidence suggests that astroglia, and possibly microglia, play an important part in regulating synaptic networking of the brain. It has also emerged that extracellular matrix (ECM) structures that enwrap synaptic connections can generate molecular signals affecting both neuronal and glial activity. Thus it appears that the mechanism of information processing in the brain, which has hitherto been associated almost exclusively with neural circuits, could also invo...

  18. Calcineurin, Synaptic Plasticity, and Memory

    Directory of Open Access Journals (Sweden)

    Carl Weitlauf

    2001-01-01

    Full Text Available A long-held hypothesis in neuroscience holds that learning and memory mechanisms involve lasting changes in synaptic weights. Multiple mechanisms for producing such changes exist, of which NMDA-receptor–dependent long-term potentiation (LTP is the most widely studied. Curiously, the relatively simple hypothesis that LTP plays a role in learning and memory has proven difficult to test. A current experimental strategy is to generate genetically altered mice with mutations in genes thought to be involved in LTP and assess the effects of these mutations both on LTP and animal behavior[1,2]. A difficulty associated with these approaches has been that they are not temporally or spatially refined. To alleviate this problem, Dr. Isabelle Mansuy and colleagues used an inducible and reversible transgene expression system in which transgene expression could be controlled on a week-to-week timescale to assess the effects of genetic reduction of the activity of a protein phosphatase known as calcineurin or PP2B in adult mouse forebrain[3,4].

  19. Spike-triggered dendritic calcium transients depend on synaptic activity in the cricket giant interneurons.

    Science.gov (United States)

    Ogawa, Hiroto; Baba, Yoshichika; Oka, Kotaro

    2002-02-15

    The relationship between electrical activity and spike-induced Ca2+ increases in dendrites was investigated in the identified wind-sensitive giant interneurons in the cricket. We applied a high-speed Ca2+ imaging technique to the giant interneurons, and succeeded in recording the transient Ca2+ increases (Ca2+ transients) induced by a single action potential, which was evoked by presynaptic stimulus to the sensory neurons. The dendritic Ca2+ transients evoked by a pair of action potentials accumulated when spike intervals were shorter than 100 ms. The amplitude of the Ca2+ transients induced by a train of spikes depended on the number of action potentials. When stimulation pulses evoking the same numbers of action potentials were separately applied to the ipsi- or contra-lateral cercal sensory nerves, the dendritic Ca2+ transients induced by these presynaptic stimuli were different in their amplitude. Furthermore, the side of presynaptic stimulation that evoked larger Ca2+ transients depended on the location of the recorded dendritic regions. This result means that the spike-triggered Ca2+ transients in dendrites depend on postsynaptic activity. It is proposed that Ca2+ entry through voltage-dependent Ca2+ channels activated by the action potentials will be enhanced by excitatory synaptic inputs at the dendrites in the cricket giant interneurons.

  20. The Impact of Stimulation Induced Short Term Synaptic Plasticity on Firing Patterns in the Globus Pallidus of the Rat

    Directory of Open Access Journals (Sweden)

    Jenia eBugaysen

    2011-03-01

    Full Text Available Electrical stimulation in the globus pallidus (GP leads to complex modulations of neuronal activity in the stimulated nucleus. Multiple in-vivo studies have demonstrated the modulation of both firing rates and patterns during and immediately following the GP stimulation. Previous in-vitro studies, together with computational studies, have suggested the involvement of short-term synaptic plasticity (STP during the stimulation. The aim of the current study was to explore in-vitro the effects of STP on neuronal activity of GP neurons during local repetitive stimulation. We recorded synaptic potentials and assessed the modulations of spontaneous firing in a postsynaptic neuron in acute brain slices via a whole-cell pipette. Low-frequency repetitive stimulation locked the firing of the neuron to the stimulus. However, high-frequency repetitive stimulation in the GP generated a biphasic modulation of the firing frequency consisting of inhibitory and excitatory phases. Using blockers of synaptic transmission, we show that GABAergic synapses mediated the inhibitory and glutamatergic synapses the excitatory part of the response. Furthermore, we report that at high stimulation frequencies both types of synapses undergo short-term depression leading to a time dependent modulation of the neuronal firing. These findings indicate that STP modulates the dynamic responses of pallidal activity during electrical stimulation, and may contribute to a better understanding of the mechanism underlying deep brain stimulation (DBS like protocols.

  1. Curcumin improves synaptic plasticity impairment induced by HIV-1gp120 V3 loop

    Institute of Scientific and Technical Information of China (English)

    Ling-ling Shen; Li-juan Yang; Ying Xu; Jun Dong; Ming-liang Jiang; Si-si Liu; Min-chun Cai; Zhong-qiu Hong; Li-qing Lin; Yan-yan Xing; Gui-lin Chen; Rui Pan

    2015-01-01

    Curcumin has been shown to significantly improve spatial memory impairment induced by HIV-1 gp120 V3 in rats, but the electrophysiological mechanism remains unknown. Using extra-cellular microelectrode recording techniques, this study conifrmed that the gp120 V3 loop could suppress long-term potentiation in the rat hippocampal CA1 region and synaptic plasticity, and that curcumin could antagonize these inhibitory effects. Using a Fura-2/AM calcium ion probe, we found that curcumin resisted the effects of the gp120 V3 loop on hippocampal synaptosomes and decreased Ca2+concentration in synaptosomes. This effect of curcumin was identical to nimodipine, suggesting that curcumin improved the inhibitory effects of gp120 on synaptic plasticity, ameliorated damage caused to the central nervous system, and might be a potential neuroprotective drug.

  2. Curcumin improves synaptic plasticity impairment induced by HIV-1gp120 V3 loop

    Directory of Open Access Journals (Sweden)

    Ling-ling Shen

    2015-01-01

    Full Text Available Curcumin has been shown to significantly improve spatial memory impairment induced by HIV-1 gp120 V3 in rats, but the electrophysiological mechanism remains unknown. Using extracellular microelectrode recording techniques, this study confirmed that the gp120 V3 loop could suppress long-term potentiation in the rat hippocampal CA1 region and synaptic plasticity, and that curcumin could antagonize these inhibitory effects. Using a Fura-2/AM calcium ion probe, we found that curcumin resisted the effects of the gp120 V3 loop on hippocampal synaptosomes and decreased Ca 2+ concentration in synaptosomes. This effect of curcumin was identical to nimodipine, suggesting that curcumin improved the inhibitory effects of gp120 on synaptic plasticity, ameliorated damage caused to the central nervous system, and might be a potential neuroprotective drug.

  3. Cytoskeletal signaling: is memory encoded in microtubule lattices by CaMKII phosphorylation?

    Directory of Open Access Journals (Sweden)

    Travis J A Craddock

    Full Text Available Memory is attributed to strengthened synaptic connections among particular brain neurons, yet synaptic membrane components are transient, whereas memories can endure. This suggests synaptic information is encoded and 'hard-wired' elsewhere, e.g. at molecular levels within the post-synaptic neuron. In long-term potentiation (LTP, a cellular and molecular model for memory, post-synaptic calcium ion (Ca²⁺ flux activates the hexagonal Ca²⁺-calmodulin dependent kinase II (CaMKII, a dodacameric holoenzyme containing 2 hexagonal sets of 6 kinase domains. Each kinase domain can either phosphorylate substrate proteins, or not (i.e. encoding one bit. Thus each set of extended CaMKII kinases can potentially encode synaptic Ca²⁺ information via phosphorylation as ordered arrays of binary 'bits'. Candidate sites for CaMKII phosphorylation-encoded molecular memory include microtubules (MTs, cylindrical organelles whose surfaces represent a regular lattice with a pattern of hexagonal polymers of the protein tubulin. Using molecular mechanics modeling and electrostatic profiling, we find that spatial dimensions and geometry of the extended CaMKII kinase domains precisely match those of MT hexagonal lattices. This suggests sets of six CaMKII kinase domains phosphorylate hexagonal MT lattice neighborhoods collectively, e.g. conveying synaptic information as ordered arrays of six "bits", and thus "bytes", with 64 to 5,281 possible bit states per CaMKII-MT byte. Signaling and encoding in MTs and other cytoskeletal structures offer rapid, robust solid-state information processing which may reflect a general code for MT-based memory and information processing within neurons and other eukaryotic cells.

  4. A Hopfield-like hippocampal CA3 neural network model for studying associative memory in Alzheimer's disease

    Institute of Scientific and Technical Information of China (English)

    Wangxiong Zhao; Qingli Qiao; Dan Wang

    2010-01-01

    Associative memory, one of the major cognitive functions in the hippocampal CA3 region, includes auto-associative memory and hetero-associative memory. Many previous studies have shown that Alzheimer's disease (AD) can lead to loss of functional synapses in the central nervous system, and associative memory functions in patients with AD are often impaired, but few studies have addressed the effect of AD on hetero-associative memory in the hippocampal CA3 region. In this study, based on a simplified anatomical structure and synaptic connections in the hippocampal CA3 region, a three-layered Hopfield-like neural network model of hippocampal CA3 was proposed and then used to simulate associative memory functions in three circumstances: normal, synaptic deletion and synaptic compensation, according to Ruppin's synaptic deletion and compensation theory. The influences of AD on hetero-associative memory were further analyzed. The simulated results showed that the established three-layered Hopfield-like neural network model of hippocampal CA3 has both auto-associative and hetero-associative memory functions. With increasing synaptic deletion level, both associative memory functions were gradually impaired and the mean firing rates of the neurons within the network model were decreased. With gradual increasing synaptic compensation, the associative memory functions of the network were improved and the mean firing rates were increased. The simulated results suggest that the Hopfield-like neural network model can effectively simulate both associative memory functions of the hippocampal CA3 region. Synaptic deletion affects both auto-associative and hetero-associative memory functions in the hippocampal CA3 region, and can also result in memory dysfunction. To some extent, synaptic compensation measures can offset two kinds of associative memory dysfunction caused by synaptic deletion in the hippocampal CA3 area.

  5. Presenilin-1 Mutation Impairs Cholinergic Modulation of Synaptic Plasticity and Suppresses NMDA Currents in Hippocampus slices

    OpenAIRE

    Wang, Yue; Greig, Nigel H.; Yu, Qian-Sheng; Mattson, Mark P.

    2008-01-01

    Presenilin-1 (PS1) mutations cause many cases of early-onset inherited Alzheimer's disease, in part, by increasing the production of neurotoxic forms of amyloid β-peptide (A β). However, Aβ -independent effects of mutant PS1 on neuronal Ca2+ homeostasis and sensitivity to excitatory neurotransmitters have been reported. Here we show that cholinergic modulation of hippocampal synaptic plasticity is impaired in PS1 mutant knockin (PS1KI) mice. Whereas activation of muscarinic receptors enhances...

  6. Biphasic influence of dexamethasone exposure on embryonic vertebrate skeleton development

    Energy Technology Data Exchange (ETDEWEB)

    Cheng, Xin; Chen, Jian-long; Ma, Zheng-lai; Zhang, Zhao-long; Lv, Shun; Mai, Dong-mei; Liu, Jia-jia [Department of Histology and Embryology, Key Laboratory for Regenerative Medicine of the Ministry of Education, School of Medicine, Jinan University, Guangzhou 510632 (China); Chuai, Manli [Division of Cell and Developmental Biology, University of Dundee, Dundee DD1 5EH (United Kingdom); Lee, Kenneth Ka Ho; Wan, Chao [Stem Cell and Regeneration Thematic Research Programme, School of Biomedical Sciences, Chinese University of Hong Kong, Shatin (Hong Kong); Yang, Xuesong, E-mail: yang_xuesong@126.com [Department of Histology and Embryology, Key Laboratory for Regenerative Medicine of the Ministry of Education, School of Medicine, Jinan University, Guangzhou 510632 (China); Institute of Fetal-Preterm Labor Medicine, Jinan University, Guangzhou 510632 (China)

    2014-11-15

    increased in mesenchymal cell mass treated by low concentration of Dex. Mmp-13 expression was obviously up-regulated by Dex in both mesenchymal cells and primary chondrocyte cultures. And Col10a1 expression was also increased by Dex exposure in chondrocyte. In summary, we have revealed that different concentrations of Dex exposure during early gestation could exert a biphasic effect on vertebrate skeletal development. - Highlights: • Chick embryos occurred shortening of the long bone following Dex exposure. • Dex suppressed chondrocytes proliferation and promoted apoptosis. • Dex exposure decreased ALP production and up-regulated Runx-2 and Mmp-13. • Dex exhibited biphasic effects on chondrogenic proliferation and nodule formation. • The hypertrophy and ossification were accelerated by Dex both in vivo and in vitro.

  7. Novel incoherent scheme for photonic generation of biphase modulated UWB signals

    DEFF Research Database (Denmark)

    Yu, Xianbin; Gibbon, Timothy Braidwood; Zibar, Darko;

    2009-01-01

    A novel incoherent scheme for generation of direct-sequence binary biphase modulated ultrawideband (UWB) signals is proposed and experimentally demonstrated. There is no requirement for pulse shaper (optical filter) in our proposed system.......A novel incoherent scheme for generation of direct-sequence binary biphase modulated ultrawideband (UWB) signals is proposed and experimentally demonstrated. There is no requirement for pulse shaper (optical filter) in our proposed system....

  8. Oscillatory three-phase flow reactor for studies of bi-phasic catalytic reactions

    OpenAIRE

    Abolhasani, Milad; Bruno, Nicholas C.; Jensen, Klavs F.

    2015-01-01

    A multi-phase flow strategy, based on oscillatory motion of a bi-phasic slug within a fluorinated ethylene propylene (FEP) tubular reactor, under inert atmosphere, is designed and developed to address mixing and mass transfer limitations associated with continuous slug flow chemistry platforms for studies of bi-phasic catalytic reactions. The technique is exemplified with C–C and C–N Pd catalyzed coupling reactions.

  9. Biphasic flow: structure and upscaling, consequences on macroscopic transport properties

    CERN Document Server

    Toussaint, Renaud; Méheust, Yves; Løvoll, Grunde; Jankov, Mihailo; Schäfer, Gerhard; Schmittbuhl, Jean

    2012-01-01

    In disordered porous media, two-phase flow of immiscible fluids (biphasic flow) is organized in patterns that sometimes exhibit fractal geometries over a range of length scales, depending on the capillary, gravitational and viscous forces at play. These forces, as well as the boundary conditions, also determine whether the flow leads to the appearance of fingering pathways, i.e., unstable flow, or not. We present here a short review of these aspects, focusing on drainage and summarizing when these flows are expected to be stable or not, what fractal dimensions can be expected, and in which range of scales. We base our review on experimental studies performed in two-dimensional Hele-Shaw cells, or addressing three dimensional porous media by use of several imaging techniques. We first present configurations in which solely capillary forces and gravity play a role. Next, we review configurations in which capillarity and viscosity are the main forces at play. Eventually, we examine how the microscopic geometry o...

  10. Biphasic oxidation of oxy-hemoglobin in bloodstains.

    Directory of Open Access Journals (Sweden)

    Rolf H Bremmer

    Full Text Available BACKGROUND: In forensic science, age determination of bloodstains can be crucial in reconstructing crimes. Upon exiting the body, bloodstains transit from bright red to dark brown, which is attributed to oxidation of oxy-hemoglobin (HbO(2 to met-hemoglobin (met-Hb and hemichrome (HC. The fractions of HbO(2, met-Hb and HC in a bloodstain can be used for age determination of bloodstains. In this study, we further analyze the conversion of HbO(2 to met-Hb and HC, and determine the effect of temperature and humidity on the conversion rates. METHODOLOGY: The fractions of HbO(2, met-Hb and HC in a bloodstain, as determined by quantitative analysis of optical reflectance spectra (450-800 nm, were measured as function of age, temperature and humidity. Additionally, Optical Coherence Tomography around 1300 nm was used to confirm quantitative spectral analysis approach. CONCLUSIONS: The oxidation rate of HbO(2 in bloodstains is biphasic. At first, the oxidation of HbO(2 is rapid, but slows down after a few hours. These oxidation rates are strongly temperature dependent. However, the oxidation of HbO(2 seems to be independent of humidity, whereas the transition of met-Hb into HC strongly depends on humidity. Knowledge of these decay rates is indispensable for translating laboratory results into forensic practice, and to enable bloodstain age determination on the crime scene.

  11. A biphasic theory for the viscoelastic behaviors of vocal fold lamina propria in stress relaxation.

    Science.gov (United States)

    Zhang, Yu; Czerwonka, Lukasz; Tao, Chao; Jiang, Jack J

    2008-03-01

    In this study, a biphasic theory is applied to investigate the viscoelastic behaviors of vocal fold lamina propria during stress relaxation. The vocal fold lamina propria tissue is described as a biphasic material composed of a solid phase and an interstitial fluid phase. The biphasic theory reveals the interaction between the solid and the fluid. For the one-dimensional case, the analytical solutions of solid displacement, fluid velocity, and stress are derived. The biphasic theory predicts the stress relaxation of the vocal fold lamina propria. The quasilinear viscoelastic model as well as its higher-order elastic parameters can be derived from this biphasic theory. Furthermore, the fluid is found to support the majority of the stress at the early stage of stress relaxation; however, when the time becomes sufficiently large, the solid eventually bears all the stress. The early fluid stress support is much higher than the eventual solid support and may be important for understanding the effects of dehydration on tissue damage. By considering the solid-fluid structure of the vocal fold lamina propria, the biphasic theory allows for a more physical theory of tissue viscoelasticity than a single phase solid description and may provide a valuable physical mechanism for the observed vocal fold rheologic behaviors.

  12. Synaptic Mechanisms of Blast Induced Brain Injury

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    Andrzej ePrzekwas

    2016-01-01

    Full Text Available Blast wave-induced traumatic brain injury (TBI is one of the most common injuries to military personnel. Brain tissue compression/tension due to blast-induced cranial deformations and shear waves due to head rotation may generate diffuse micro-damage to neuro-axonal structures and trigger a cascade of neurobiological events culminating in cognitive and neurodegenerative disorders. Although diffuse axonal injury is regarded as a signature wound of mild TBI (mTBI, blast loads may also cause synaptic injury wherein neuronal synapses are stretched and sheared. This synaptic injury may result in temporary disconnect of the neural circuitry and transient loss in neuronal communication. We hypothesize that mTBI symptoms such as loss of consciousness or dizziness, which start immediately after the insult could be attributed to synaptic injury. Although empirical evidence is beginning to emerge; the detailed mechanisms underlying synaptic injury are still elusive. Coordinated in vitro - in vivo experiments and mathematical modeling studies can shed light into the synaptic injury mechanisms and their role in the potentiation of mTBI symptoms.

  13. Synaptic connectivity in engineered neuronal networks.

    Science.gov (United States)

    Molnar, Peter; Kang, Jung-Fong; Bhargava, Neelima; Das, Mainak; Hickman, James J

    2014-01-01

    We have developed a method to organize cells in dissociated cultures using engineered chemical clues on a culture surface and determined their connectivity patterns. Although almost all elements of the synaptic transmission machinery can be studied separately in single cell models in dissociated cultures, the complex physiological interactions between these elements are usually lost. Thus, factors affecting synaptic transmission are generally studied in organotypic cultures, brain slices, or in vivo where the cellular architecture generally remains intact. However, by utilizing engineered neuronal networks complex phenomenon such as synaptic transmission or synaptic plasticity can be studied in a simple, functional, cell culture-based system. We have utilized self-assembled monolayers and photolithography to create the surface templates. Embryonic hippocampal cells, plated on the resultant patterns in serum-free medium, followed the surface clues and formed the engineered neuronal networks. Basic whole-cell patch-clamp electrophysiology was applied to characterize the synaptic connectivity in these engineered two-cell networks. The same technology has been used to pattern other cell types such as cardiomyocytes or skeletal muscle fibers.

  14. Stabilizing ER Ca2+ channel function as an early preventative strategy for Alzheimer's disease.

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    Shreaya Chakroborty

    Full Text Available Alzheimer's disease (AD is a devastating neurodegenerative condition with no known cure. While current therapies target late-stage amyloid formation and cholinergic tone, to date, these strategies have proven ineffective at preventing disease progression. The reasons for this may be varied, and could reflect late intervention, or, that earlier pathogenic mechanisms have been overlooked and permitted to accelerate the disease process. One such example would include synaptic pathology, the disease component strongly associated with cognitive impairment. Dysregulated Ca(2+ homeostasis may be one of the critical factors driving synaptic dysfunction. One of the earliest pathophysiological indicators in mutant presenilin (PS AD mice is increased intracellular Ca(2+ signaling, predominantly through the ER-localized inositol triphosphate (IP(3 and ryanodine receptors (RyR. In particular, the RyR-mediated Ca(2+ upregulation within synaptic compartments is associated with altered synaptic homeostasis and network depression at early (presymptomatic AD stages. Here, we offer an alternative approach to AD therapeutics by stabilizing early pathogenic mechanisms associated with synaptic abnormalities. We targeted the RyR as a means to prevent disease progression, and sub-chronically treated AD mouse models (4-weeks with a novel formulation of the RyR inhibitor, dantrolene. Using 2-photon Ca(2+ imaging and patch clamp recordings, we demonstrate that dantrolene treatment fully normalizes ER Ca(2+ signaling within somatic and dendritic compartments in early and later-stage AD mice in hippocampal slices. Additionally, the elevated RyR2 levels in AD mice are restored to control levels with dantrolene treatment, as are synaptic transmission and synaptic plasticity. Aβ deposition within the cortex and hippocampus is also reduced in dantrolene-treated AD mice. In this study, we highlight the pivotal role of Ca(2+ aberrations in AD, and propose a novel strategy to

  15. NMDA receptors mediate synaptic competition in culture.

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    Kevin She

    Full Text Available BACKGROUND: Activity through NMDA type glutamate receptors sculpts connectivity in the developing nervous system. This topic is typically studied in the visual system in vivo, where activity of inputs can be differentially regulated, but in which individual synapses are difficult to visualize and mechanisms governing synaptic competition can be difficult to ascertain. Here, we develop a model of NMDA-receptor dependent synaptic competition in dissociated cultured hippocampal neurons. METHODOLOGY/PRINCIPAL FINDINGS: GluN1 -/- (KO mouse hippocampal neurons lacking the essential NMDA receptor subunit were cultured alone or cultured in defined ratios with wild type (WT neurons. The absence of functional NMDA receptors did not alter neuron survival. Synapse development was assessed by immunofluorescence for postsynaptic PSD-95 family scaffold and apposed presynaptic vesicular glutamate transporter VGlut1. Synapse density was specifically enhanced onto minority wild type neurons co-cultured with a majority of GluN1 -/- neighbour neurons, both relative to the GluN1 -/- neighbours and relative to sister pure wild type cultures. This form of synaptic competition was dependent on NMDA receptor activity and not conferred by the mere physical presence of GluN1. In contrast to these results in 10% WT and 90% KO co-cultures, synapse density did not differ by genotype in 50% WT and 50% KO co-cultures or in 90% WT and 10% KO co-cultures. CONCLUSIONS/SIGNIFICANCE: The enhanced synaptic density onto NMDA receptor-competent neurons in minority coculture with GluN1 -/- neurons represents a cell culture paradigm for studying synaptic competition. Mechanisms involved may include a retrograde 'reward' signal generated by WT neurons, although in this paradigm there was no 'punishment' signal against GluN1 -/- neurons. Cell culture assays involving such defined circuits may help uncover the rules and mechanisms of activity-dependent synaptic competition in the

  16. Leptin Induces a Novel Form of NMDA Receptor-Dependent LTP at Hippocampal Temporoammonic-CA1 Synapses 1,2,3

    OpenAIRE

    Luo, Xiao; McGregor, Gemma; Irving, Andrew J; Harvey, Jenni

    2015-01-01

    Abstract It is well documented that the hormone leptin regulates many central functions and that hippocampal CA1 pyramidal neurons are a key target for leptin action. Indeed, leptin modulates excitatory synaptic transmission and synaptic plasticity at the Schaffer-collateral input to CA1 neurons. However the impact of leptin on the direct temporoammonic (TA) input to CA1 neurons is not known. Here we show that leptin evokes a long-lasting increase [long-term potentiation (LTP)] in excitatory ...

  17. Imaging synaptic zinc: promises and perils.

    Science.gov (United States)

    Kay, Alan R

    2006-04-01

    It is well established that some excitatory nerve terminals have high concentrations of Zn(2+) in their synaptic vesicles. For some time, it has been believed that synaptic Zn(2+) is released during neurotransmission and acts as a neuromodulator. Fluorescent Zn(2+) indicators that do not penetrate membranes offer the prospect of rendering the release of Zn(2+) visible. Here, I take a critical look at fluorimetric imaging experiments devised to determine whether Zn(2+) is released and show that they are particularly susceptible to artifacts. Moreover, I will argue that recent experiments suggest that, rather than being released, Zn(2+) is presented to the extracellular space firmly coordinated to presynaptic macromolecules.

  18. Design and evaluation of lornoxicam bilayered tablets for biphasic release

    Directory of Open Access Journals (Sweden)

    Songa Ambedkar Sunil

    2012-12-01

    Full Text Available The objective of the present investigation was to develop bilayered tablets of lornoxicam to achieve biphasic release pattern. A bilayered tablet, consisting of an immediate and controlled release layer, was prepared by direct compression technique. The controlled release effect was achieved by using various hydrophilic natural, semi synthetic and synthetic controlled release polymers such as xanthan gum, hydroxypropyl methylcellulose (HPMC and polyethylene oxide (PEO to modulate the release of the drug. The in vitro drug release profiles showed the biphasic release behavior in which the immediate release (IR layer containing the lornoxicam was released within 15 minutes, whereas the controlled release (CR layer controlled the drug release for up to 24 h. All the bilayered tablets formulated have followed the zero order release with non-Fickian diffusion controlled release mechanism after the initial burst release. FTIR studies revealed that there was no interaction between the drug and polymers used in the study. Statistical analysis (ANOVA showed no significant difference in the cumulative amount of drug release after 15 min, but significant difference (p O objetivo do presente trabalho foi desenvolver comprimidos bicamada de lornoxicam para atingir padrão de liberação bifásica. Preparou-se, por compressão direta, comprimido bicamada, consistindo de uma camada de liberação imediata e uma de liberação controlada. A liberação controlada foi obtida pelo uso de vários polímeros naturais hidrofílicos, semi-sintéticos e sintéticos, tais como goma xantana, hidroxipropilmetil celulose (HPMC e óxido de polietileno (PEO para modular a liberação do fármaco. Os perfis de liberação in vitro mostraram comportamento bifásico em que a camada de liberação imediata (IR contendo lornoxicam foi liberada em 15 minutos, enquanto a camada de liberação controlada (CR liberou o fármaco em mais de 24 horas, Todos os comprimidos bicamada

  19. Short-term environmental enrichment enhances synaptic plasticity in hippocampal slices from aged rats.

    Science.gov (United States)

    Stein, Liana R; O'Dell, Kazuko A; Funatsu, Michiyo; Zorumski, Charles F; Izumi, Yukitoshi

    2016-08-01

    Age-associated changes in cognition are mirrored by impairments in cellular models of memory and learning, such as long-term potentiation (LTP) and long-term depression (LTD). In young rodents, environmental enrichment (EE) can enhance memory, alter LTP and LTD, as well as reverse cognitive deficits induced by aging. Whether short-term EE can benefit cognition and synaptic plasticity in aged rodents is unclear. Here, we tested if short-term EE could overcome age-associated impairments in induction of LTP and LTD. LTP and LTD could not be induced in the CA1 region of hippocampal slices in control, aged rats using standard stimuli that are highly effective in young rats. However, exposure of aged littermates to EE for three weeks enabled successful induction of LTP and LTD. EE-facilitated LTP was dependent upon N-methyl-d-aspartate receptors (NMDARs). These alterations in synaptic plasticity occurred with elevated levels of phosphorylated cAMP response element-binding protein and vascular endothelial growth factor, but in the absence of changes in several other synaptic and cellular markers. Importantly, our study suggests that even a relatively short period of EE is sufficient to alter synaptic plasticity and molecular markers linked to cognitive function in aged animals. PMID:27208617

  20. Nuclear calcium signaling induces expression of the synaptic organizers Lrrtm1 and Lrrtm2.

    Science.gov (United States)

    Hayer, Stefanie N; Bading, Hilmar

    2015-02-27

    Calcium transients in the cell nucleus evoked by synaptic activity in hippocampal neurons function as a signaling end point in synapse-to-nucleus communication. As an important regulator of neuronal gene expression, nuclear calcium is involved in the conversion of synaptic stimuli into functional and structural changes of neurons. Here we identify two synaptic organizers, Lrrtm1 and Lrrtm2, as targets of nuclear calcium signaling. Expression of both Lrrtm1 and Lrrtm2 increased in a synaptic NMDA receptor- and nuclear calcium-dependent manner in hippocampal neurons within 2-4 h after the induction of action potential bursting. Induction of Lrrtm1 and Lrrtm2 occurred independently of the need for new protein synthesis and required calcium/calmodulin-dependent protein kinases and the nuclear calcium signaling target CREB-binding protein. Analysis of reporter gene constructs revealed a functional cAMP response element in the proximal promoter of Lrrtm2, indicating that at least Lrrtm2 is regulated by the classical nuclear Ca(2+)/calmodulin-dependent protein kinase IV-CREB/CREB-binding protein pathway. These results suggest that one mechanism by which nuclear calcium signaling controls neuronal network function is by regulating the expression of Lrrtm1 and Lrrtm2.

  1. Bi-directional modulation of AMPA receptor unitary conductance by synaptic activity

    Directory of Open Access Journals (Sweden)

    Matthews Paul

    2004-11-01

    Full Text Available Abstract Background Knowledge of how synapses alter their efficiency of communication is central to the understanding of learning and memory. The most extensively studied forms of synaptic plasticity are long-term potentiation (LTP and its counterpart long-term depression (LTD of AMPA receptor-mediated synaptic transmission. In the CA1 region of the hippocampus, it has been shown that LTP often involves a rapid increase in the unitary conductance of AMPA receptor channels. However, LTP can also occur in the absence of any alteration in AMPA receptor unitary conductance. In the present study we have used whole-cell dendritic recording, failures analysis and non-stationary fluctuation analysis to investigate the mechanism of depotentiation of LTP. Results We find that when LTP involves an increase in unitary conductance, subsequent depotentiation invariably involves the return of unitary conductance to pre-LTP values. In contrast, when LTP does not involve a change in unitary conductance then depotentiation also occurs in the absence of any change in unitary conductance, indicating a reduction in the number of activated receptors as the most likely mechanism. Conclusions These data show that unitary conductance can be bi-directionally modified by synaptic activity. Furthermore, there are at least two distinct mechanisms to restore synaptic strength from a potentiated state, which depend upon the mechanism of the previous potentiation.

  2. Enriched environment ameliorates depression-induced cognitive deficits and restores abnormal hippocampal synaptic plasticity.

    Science.gov (United States)

    Mahati, K; Bhagya, V; Christofer, T; Sneha, A; Shankaranarayana Rao, B S

    2016-10-01

    Severe depression compromises structural and functional integrity of the brain and results in impaired learning and memory, maladaptive synaptic plasticity as well as degenerative changes in the hippocampus and amygdala. The precise mechanisms underlying cognitive dysfunctions in depression remain largely unknown. On the other hand, enriched environment (EE) offers beneficial effects on cognitive functions, synaptic plasticity in the hippocampus. However, the effect of EE on endogenous depression associated cognitive dysfunction has not been explored. Accordingly, we have attempted to address this issue by investigating behavioural, structural and synaptic plasticity mechanisms in an animal model of endogenous depression after exposure to enriched environment. Our results demonstrate that depression is associated with impaired spatial learning and enhanced anxiety-like behaviour which is correlated with hypotrophy of the dentate gyrus and amygdalar hypertrophy. We also observed a gross reduction in the hippocampal long-term potentiation (LTP). We report a complete behavioural recovery with reduced indices of anhedonia and behavioural despair, reduced anxiety-like behaviour and improved spatial learning along with a complete restoration of dentate gyrus and amygdalar volumes in depressive rats subjected to EE. Enrichment also facilitated CA3-Schaffer collateral LTP. Our study convincingly proves that depression-induces learning deficits and impairs hippocampal synaptic plasticity. It also highlights the role of environmental stimuli in restoring depression-induced cognitive deficits which might prove vital in outlining more effective strategies to treat major depressive disorders. PMID:27555234

  3. Upregulation of transmitter release probability improves a conversion of synaptic analogue signals into neuronal digital spikes

    Directory of Open Access Journals (Sweden)

    Yu Jiandong

    2012-08-01

    Full Text Available Abstract Action potentials at the neurons and graded signals at the synapses are primary codes in the brain. In terms of their functional interaction, the studies were focused on the influence of presynaptic spike patterns on synaptic activities. How the synapse dynamics quantitatively regulates the encoding of postsynaptic digital spikes remains unclear. We investigated this question at unitary glutamatergic synapses on cortical GABAergic neurons, especially the quantitative influences of release probability on synapse dynamics and neuronal encoding. Glutamate release probability and synaptic strength are proportionally upregulated by presynaptic sequential spikes. The upregulation of release probability and the efficiency of probability-driven synaptic facilitation are strengthened by elevating presynaptic spike frequency and Ca2+. The upregulation of release probability improves spike capacity and timing precision at postsynaptic neuron. These results suggest that the upregulation of presynaptic glutamate release facilitates a conversion of synaptic analogue signals into digital spikes in postsynaptic neurons, i.e., a functional compatibility between presynaptic and postsynaptic partners.

  4. Flexible Proton-Gated Oxide Synaptic Transistors on Si Membrane.

    Science.gov (United States)

    Zhu, Li Qiang; Wan, Chang Jin; Gao, Ping Qi; Liu, Yang Hui; Xiao, Hui; Ye, Ji Chun; Wan, Qing

    2016-08-24

    Ion-conducting materials have received considerable attention for their applications in fuel cells, electrochemical devices, and sensors. Here, flexible indium zinc oxide (InZnO) synaptic transistors with multiple presynaptic inputs gated by proton-conducting phosphorosilicate glass-based electrolyte films are fabricated on ultrathin Si membranes. Transient characteristics of the proton gated InZnO synaptic transistors are investigated, indicating stable proton-gating behaviors. Short-term synaptic plasticities are mimicked on the proposed proton-gated synaptic transistors. Furthermore, synaptic integration regulations are mimicked on the proposed synaptic transistor networks. Spiking logic modulations are realized based on the transition between superlinear and sublinear synaptic integration. The multigates coupled flexible proton-gated oxide synaptic transistors may be interesting for neuroinspired platforms with sophisticated spatiotemporal information processing. PMID:27471861

  5. Synaptic plasticity and the warburg effect

    KAUST Repository

    Magistretti, Pierre J.

    2014-01-01

    Functional brain imaging studies show that in certain brain regions glucose utilization exceeds oxygen consumption, indicating the predominance of aerobic glycolysis. In this issue, Goyal et al. (2014) report that this metabolic profile is associated with an enrichment in the expression of genes involved in synaptic plasticity and remodeling processes. © 2014 Elsevier Inc.

  6. Retinal synaptic regeneration via microfluidic guiding channels.

    Science.gov (United States)

    Su, Ping-Jung; Liu, Zongbin; Zhang, Kai; Han, Xin; Saito, Yuki; Xia, Xiaojun; Yokoi, Kenji; Shen, Haifa; Qin, Lidong

    2015-08-28

    In vitro culture of dissociated retinal neurons is an important model for investigating retinal synaptic regeneration (RSR) and exploring potentials in artificial retina. Here, retinal precursor cells were cultured in a microfluidic chip with multiple arrays of microchannels in order to reconstruct the retinal neuronal synapse. The cultured retinal cells were physically connected through microchannels. Activation of electric signal transduction by the cells through the microchannels was demonstrated by administration of glycinergic factors. In addition, an image-based analytical method was used to quantify the synaptic connections and to assess the kinetics of synaptic regeneration. The rate of RSR decreased significantly below 100 μM of inhibitor glycine and then approached to a relatively constant level at higher concentrations. Furthermore, RSR was enhanced by chemical stimulation with potassium chloride. Collectively, the microfluidic synaptic regeneration chip provides a novel tool for high-throughput investigation of RSR at the cellular level and may be useful in quality control of retinal precursor cell transplantation.

  7. Retinal synaptic regeneration via microfluidic guiding channels.

    Science.gov (United States)

    Su, Ping-Jung; Liu, Zongbin; Zhang, Kai; Han, Xin; Saito, Yuki; Xia, Xiaojun; Yokoi, Kenji; Shen, Haifa; Qin, Lidong

    2015-01-01

    In vitro culture of dissociated retinal neurons is an important model for investigating retinal synaptic regeneration (RSR) and exploring potentials in artificial retina. Here, retinal precursor cells were cultured in a microfluidic chip with multiple arrays of microchannels in order to reconstruct the retinal neuronal synapse. The cultured retinal cells were physically connected through microchannels. Activation of electric signal transduction by the cells through the microchannels was demonstrated by administration of glycinergic factors. In addition, an image-based analytical method was used to quantify the synaptic connections and to assess the kinetics of synaptic regeneration. The rate of RSR decreased significantly below 100 μM of inhibitor glycine and then approached to a relatively constant level at higher concentrations. Furthermore, RSR was enhanced by chemical stimulation with potassium chloride. Collectively, the microfluidic synaptic regeneration chip provides a novel tool for high-throughput investigation of RSR at the cellular level and may be useful in quality control of retinal precursor cell transplantation. PMID:26314276

  8. Fragile X mental retardation protein and synaptic plasticity

    OpenAIRE

    Sidorov, Michael S.; Auerbach, Benjamin D.; Bear, Mark F.

    2013-01-01

    Loss of the translational repressor FMRP causes Fragile X syndrome. In healthy neurons, FMRP modulates the local translation of numerous synaptic proteins. Synthesis of these proteins is required for the maintenance and regulation of long-lasting changes in synaptic strength. In this role as a translational inhibitor, FMRP exerts profound effects on synaptic plasticity.

  9. Calcineurin proteolysis in astrocytes: Implications for impaired synaptic function.

    Science.gov (United States)

    Pleiss, Melanie M; Sompol, Pradoldej; Kraner, Susan D; Abdul, Hafiz Mohmmad; Furman, Jennifer L; Guttmann, Rodney P; Wilcock, Donna M; Nelson, Peter T; Norris, Christopher M

    2016-09-01

    Mounting evidence suggests that astrocyte activation, found in most forms of neural injury and disease, is linked to the hyperactivation of the protein phosphatase calcineurin. In many tissues and cell types, calcineurin hyperactivity is the direct result of limited proteolysis. However, little is known about the proteolytic status of calcineurin in activated astrocytes. Here, we developed a polyclonal antibody to a high activity calcineurin proteolytic fragment in the 45-48kDa range (ΔCN) for use in immunohistochemical applications. When applied to postmortem human brain sections, the ΔCN antibody intensely labeled cell clusters in close juxtaposition to amyloid deposits and microinfarcts. Many of these cells exhibited clear activated astrocyte morphology. The expression of ΔCN in astrocytes near areas of pathology was further confirmed using confocal microscopy. Multiple NeuN-positive cells, particularly those within microinfarct core regions, also labeled positively for ΔCN. This observation suggests that calcineurin proteolysis can also occur within damaged or dying neurons, as reported in other studies. When a similar ΔCN fragment was selectively expressed in hippocampal astrocytes of intact rats (using adeno-associated virus), we observed a significant reduction in the strength of CA3-CA1 excitatory synapses, indicating that the hyperactivation of astrocytic calcineurin is sufficient for disrupting synaptic function. Together, these results suggest that proteolytic activation of calcineurin in activated astrocytes may be a central mechanism for driving and/or exacerbating neural dysfunction during neurodegenerative disease and injury. PMID:27212416

  10. Influence of saline solution on hydration behavior of β-dicalcium silicate in comparison with biphasic calcium phosphate/hydroxyapatite bio-ceramics

    International Nuclear Information System (INIS)

    The influence of using saline solution as mixing and curing liquid on some characteristics of β-dicalcium silicate (β-C2S) and biphasic compound tri-calcium phosphate/hydroxyapatite (TCP/HAp) bio-ceramics was investigated. β-C2S (27–30 nm) was prepared by solid state reaction at 1450 °C, while biphasic compound TCP/HAp (7–15 nm) was synthesized from an aqueous solution of Ca(NO3)2·4H2O and (NH4)2HPO4·12H2O by chemical precipitation method. Setting times, compressive strength, pH values, X-ray diffraction analysis, infrared spectroscopy, scanning electron microscopy (SEM) were investigated. The evaluation of cytotoxicity of both calcium silicate and biphasic compounds to human gingival fibroblasts was carried out. The use of saline solution as mixing and immersing liquid shortened the setting time for the two bio-cements. TCP/HAp did not show any mechanical strength but β-C2S showed good strength values. Both synthesized compounds showed a moderate cytotoxicity and both materials were effective in a no significant way. - Highlights: • The dissolution and hydration of β-C2S and TCP/HAp in distilled water and saline solution were studied. • TCP/HAp did not show mechanical strength, while β-C2S showed good mechanical strength. • The use of saline solution did enhances the dissolution & hydration rate. • An increase in pH values was detected when using saline solution. • Both materials showed a moderate cytotoxicity in no significant way

  11. Influence of saline solution on hydration behavior of β-dicalcium silicate in comparison with biphasic calcium phosphate/hydroxyapatite bio-ceramics

    Energy Technology Data Exchange (ETDEWEB)

    Radwan, M.M., E-mail: mmahmoudradwan@yahoo.com [Ceramics Dept, National Research Centre, Cairo (Egypt); Abd El-Hamid, H.K. [Ceramics Dept, National Research Centre, Cairo (Egypt); Mohamed, A.F. [The Holding Company for Production of Vaccines, Sera and Drugs (EGYVAC) (Egypt)

    2015-12-01

    The influence of using saline solution as mixing and curing liquid on some characteristics of β-dicalcium silicate (β-C{sub 2}S) and biphasic compound tri-calcium phosphate/hydroxyapatite (TCP/HAp) bio-ceramics was investigated. β-C{sub 2}S (27–30 nm) was prepared by solid state reaction at 1450 °C, while biphasic compound TCP/HAp (7–15 nm) was synthesized from an aqueous solution of Ca(NO{sub 3}){sub 2}·4H{sub 2}O and (NH{sub 4}){sub 2}HPO{sub 4}·12H{sub 2}O by chemical precipitation method. Setting times, compressive strength, pH values, X-ray diffraction analysis, infrared spectroscopy, scanning electron microscopy (SEM) were investigated. The evaluation of cytotoxicity of both calcium silicate and biphasic compounds to human gingival fibroblasts was carried out. The use of saline solution as mixing and immersing liquid shortened the setting time for the two bio-cements. TCP/HAp did not show any mechanical strength but β-C{sub 2}S showed good strength values. Both synthesized compounds showed a moderate cytotoxicity and both materials were effective in a no significant way. - Highlights: • The dissolution and hydration of β-C{sub 2}S and TCP/HAp in distilled water and saline solution were studied. • TCP/HAp did not show mechanical strength, while β-C{sub 2}S showed good mechanical strength. • The use of saline solution did enhances the dissolution & hydration rate. • An increase in pH values was detected when using saline solution. • Both materials showed a moderate cytotoxicity in no significant way.

  12. Differential Modulation of Synaptic Strength and Timing Regulate Synaptic Efficacy in a Motor Network

    OpenAIRE

    Bruce R Johnson; Brown, Jessica M; Kvarta, Mark D.; Lu, Jay Y. J.; Schneider, Lauren R.; Nadim, Farzan; Harris-Warrick, Ronald M

    2010-01-01

    Neuromodulators modify network output by altering neuronal firing properties and synaptic strength at multiple sites; however, the functional importance of each site is often unclear. We determined the importance of monoamine modulation of a single synapse for regulation of network cycle frequency in the oscillatory pyloric network of the lobster. The pacemaker kernel of the pyloric network receives only one chemical synaptic feedback, an inhibitory synapse from the lateral pyloric (LP) neuro...

  13. A role for calcium-permeable AMPA receptors in synaptic plasticity and learning.

    Directory of Open Access Journals (Sweden)

    Brian J Wiltgen

    Full Text Available A central concept in the field of learning and memory is that NMDARs are essential for synaptic plasticity and memory formation. Surprisingly then, multiple studies have found that behavioral experience can reduce or eliminate the contribution of these receptors to learning. The cellular mechanisms that mediate learning in the absence of NMDAR activation are currently unknown. To address this issue, we examined the contribution of Ca(2+-permeable AMPARs to learning and plasticity in the hippocampus. Mutant mice were engineered with a conditional genetic deletion of GluR2 in the CA1 region of the hippocampus (GluR2-cKO mice. Electrophysiology experiments in these animals revealed a novel form of long-term potentiation (LTP that was independent of NMDARs and mediated by GluR2-lacking Ca(2+-permeable AMPARs. Behavioral analyses found that GluR2-cKO mice were impaired on multiple hippocampus-dependent learning tasks that required NMDAR activation. This suggests that AMPAR-mediated LTP interferes with NMDAR-dependent plasticity. In contrast, NMDAR-independent learning was normal in knockout mice and required the activation of Ca(2+-permeable AMPARs. These results suggest that GluR2-lacking AMPARs play a functional and previously unidentified role in learning; they appear to mediate changes in synaptic strength that occur after plasticity has been established by NMDARs.

  14. Reduced endogenous Ca2+ buffering speeds active zone Ca2+ signaling.

    Science.gov (United States)

    Delvendahl, Igor; Jablonski, Lukasz; Baade, Carolin; Matveev, Victor; Neher, Erwin; Hallermann, Stefan

    2015-06-01

    Fast synchronous neurotransmitter release at the presynaptic active zone is triggered by local Ca(2+) signals, which are confined in their spatiotemporal extent by endogenous Ca(2+) buffers. However, it remains elusive how rapid and reliable Ca(2+) signaling can be sustained during repetitive release. Here, we established quantitative two-photon Ca(2+) imaging in cerebellar mossy fiber boutons, which fire at exceptionally high rates. We show that endogenous fixed buffers have a surprisingly low Ca(2+)-binding ratio (∼ 15) and low affinity, whereas mobile buffers have high affinity. Experimentally constrained modeling revealed that the low endogenous buffering promotes fast clearance of Ca(2+) from the active zone during repetitive firing. Measuring Ca(2+) signals at different distances from active zones with ultra-high-resolution confirmed our model predictions. Our results lead to the concept that reduced Ca(2+) buffering enables fast active zone Ca(2+) signaling, suggesting that the strength of endogenous Ca(2+) buffering limits the rate of synchronous synaptic transmission. PMID:26015575

  15. Trans-synaptic spread of tau pathology in vivo.

    Directory of Open Access Journals (Sweden)

    Li Liu

    Full Text Available Tauopathy in the brain of patients with Alzheimer's disease starts in the entorhinal cortex (EC and spreads anatomically in a defined pattern. To test whether pathology initiating in the EC spreads through the brain along synaptically connected circuits, we have generated a transgenic mouse model that differentially expresses pathological human tau in the EC and we have examined the distribution of tau pathology at different timepoints. In relatively young mice (10-11 months old, human tau was present in some cell bodies, but it was mostly observed in axons within the superficial layers of the medial and lateral EC, and at the terminal zones of the perforant pathway. In old mice (>22 months old, intense human tau immunoreactivity was readily detected not only in neurons in the superficial layers of the EC, but also in the subiculum, a substantial number of hippocampal pyramidal neurons especially in CA1, and in dentate gyrus granule cells. Scattered immunoreactive neurons were also seen in the deeper layers of the EC and in perirhinal and secondary somatosensory cortex. Immunoreactivity with the conformation-specific tau antibody MC1 correlated with the accumulation of argyrophilic material seen in old, but not young mice. In old mice, axonal human tau immunoreactivity, especially at the endzones of the perforant pathway, was greatly reduced. Relocalization of tau from axons to somatodendritic compartments and propagation of tauopathy to regions outside of the EC correlated with mature tangle formation in neurons in the EC as revealed by thioflavin-S staining. Our data demonstrate propagation of pathology from the EC and support a trans-synaptic mechanism of spread along anatomically connected networks, between connected and vulnerable neurons. In general, the mouse recapitulates the tauopathy that defines the early stages of AD and provides a model for testing mechanisms and functional outcomes associated with disease progression.

  16. The temporal characteristics of Ca2+ entry through L-type and T-type Ca2+ channels shape exocytosis efficiency in chick auditory hair cells during development.

    Science.gov (United States)

    Levic, Snezana; Dulon, Didier

    2012-12-01

    During development, synaptic exocytosis by cochlear hair cells is first initiated by patterned spontaneous Ca(2+) spikes and, at the onset of hearing, by sound-driven graded depolarizing potentials. The molecular reorganization occurring in the hair cell synaptic machinery during this developmental transition still remains elusive. We characterized the changes in biophysical properties of voltage-gated Ca(2+) currents and exocytosis in developing auditory hair cells of a precocial animal, the domestic chick. We found that immature chick hair cells (embryonic days 10-12) use two types of Ca(2+) currents to control exocytosis: low-voltage-activating, rapidly inactivating (mibefradil sensitive) T-type Ca(2+) currents and high-voltage-activating, noninactivating (nifedipine sensitive) L-type currents. Exocytosis evoked by T-type Ca(2+) current displayed a fast release component (RRP) but lacked the slow sustained release component (SRP), suggesting an inefficient recruitment of distant synaptic vesicles by this transient Ca(2+) current. With maturation, the participation of L-type Ca(2+) currents to exocytosis largely increased, inducing a highly Ca(2+) efficient recruitment of an RRP and an SRP component. Notably, L-type-driven exocytosis in immature hair cells displayed higher Ca(2+) efficiency when triggered by prerecorded native action potentials than by voltage steps, whereas similar efficiency for both protocols was found in mature hair cells. This difference likely reflects a tighter coupling between release sites and Ca(2+) channels in mature hair cells. Overall, our results suggest that the temporal characteristics of Ca(2+) entry through T-type and L-type Ca(2+) channels greatly influence synaptic release by hair cells during cochlear development.

  17. Stochastic single-molecule dynamics of synaptic membrane protein domains

    CERN Document Server

    Kahraman, Osman; Haselwandter, Christoph A

    2016-01-01

    Motivated by single-molecule experiments on synaptic membrane protein domains, we use a stochastic lattice model to study protein reaction and diffusion processes in crowded membranes. We find that the stochastic reaction-diffusion dynamics of synaptic proteins provide a simple physical mechanism for collective fluctuations in synaptic domains, the molecular turnover observed at synaptic domains, key features of the single-molecule trajectories observed for synaptic proteins, and spatially inhomogeneous protein lifetimes at the cell membrane. Our results suggest that central aspects of the single-molecule and collective dynamics observed for membrane protein domains can be understood in terms of stochastic reaction-diffusion processes at the cell membrane.

  18. Ca(2+ permeable AMPA receptor induced long-term potentiation requires PI3/MAP kinases but not Ca/CaM-dependent kinase II.

    Directory of Open Access Journals (Sweden)

    Suhail Asrar

    Full Text Available Ca(2+ influx via GluR2-lacking Ca(2+-permeable AMPA glutamate receptors (CP-AMPARs can trigger changes in synaptic efficacy in both interneurons and principle neurons, but the underlying mechanisms remain unknown. We took advantage of genetically altered mice with no or reduced GluR2, thus allowing the expression of synaptic CP-AMPARs, to investigate the molecular signaling process during CP-AMPAR-induced synaptic plasticity at CA1 synapses in the hippocampus. Utilizing electrophysiological techniques, we demonstrated that these receptors were capable of inducing numerous forms of long-term potentiation (referred to as CP-AMPAR dependent LTP through a number of different induction protocols, including high-frequency stimulation (HFS and theta-burst stimulation (TBS. This included a previously undemonstrated form of protein-synthesis dependent late-LTP (L-LTP at CA1 synapses that is NMDA-receptor independent. This form of plasticity was completely blocked by the selective CP-AMPAR inhibitor IEM-1460, and found to be dependent on postsynaptic Ca(2+ ions through calcium chelator (BAPTA studies. Surprisingly, Ca/CaM-dependent kinase II (CaMKII, the key protein kinase that is indispensable for NMDA-receptor dependent LTP at CA1 synapses appeared to be not required for the induction of CP-AMPAR dependent LTP due to the lack of effect of two separate pharmacological inhibitors (KN-62 and staurosporine on this form of potentiation. Both KN-62 and staurosporine strongly inhibited NMDA-receptor dependent LTP in control studies. In contrast, inhibitors for PI3-kinase (LY294002 and wortmannin or the MAPK cascade (PD98059 and U0126 significantly attenuated this CP-AMPAR-dependent LTP. Similarly, postsynaptic infusion of tetanus toxin (TeTx light chain, an inhibitor of exocytosis, also had a significant inhibitory effect on this form of LTP. These results suggest that distinct synaptic signaling underlies GluR2-lacking CP-AMPAR-dependent LTP, and reinforces

  19. Apomorphine-induced biphasic circling behaviour in 6-hydroxydopamine-lesioned rats. A pharmacological kindling phenomenon.

    Science.gov (United States)

    Coward, D M

    1983-06-01

    Factors governing the development of apomorphine-induced biphasic circling behaviour in rats having unilateral 6-hydroxydopamine lesions of the substantia nigra were investigated. It was found that a post-lesion time of at least 2--3 weeks and the repeated exposure to apomorphine were essential for its development. Optimal results were obtained when animals received weekly apomorphine, 0.05 mg/kg sc, in post-lesion weeks 6, 7 and 8. Pretreatment with haloperidol, 1.0 and 2.0 mg/kg ip 1 h beforehand in post-lesion week 9, converted the biphasic response into an enhanced, uniphasic one. The findings suggest that the development of the biphasic response to apomorphine is a multi-factorial process representing a pharmacological kindling phenomenon.

  20. Bi-phasic Simulation of Metal Injection Moulding:Constitutive Determinations

    Institute of Scientific and Technical Information of China (English)

    Liu Baosheng(柳葆生); Barriere Thierry; Gelin Jean-Claude

    2003-01-01

    To predict the segregation effect in metal injection moulding (MIM) injection, a bi-phasic model based on mixture theory is adopted in simulation. An explicit algorithm is developed and realized by the authors, which conducts the simulation to be a cost-effective tool in MIM technology. In case of the bi-phasic simulation, the viscosity behaviours are necessary to be determined for the flows of each phase while only the viscosity of mixture is measurable by tests. It is a crucial problem for application of the bi-phasic simulation of MIM injection. A reasonable method is hence analysed and proposed to determine the viscosity behaviours of each phase. Even though this method may be furthermore modified in the future, it results in the practical simulation of segregation effects with reasonable parameters. The simulation results are compared with the measurements on injected specimens.

  1. Is there an Optimal Shape of the Defibrillation Shock: Constant Current vs. Pulsed Biphasic Waveforms

    OpenAIRE

    Ivan Dotsinsky; Tsvetan Mudrov; Vessela Krasteva; Jecho Kostov

    2013-01-01

    Three waveforms for transthoracic defibrillation are assessed and compared: the Pulsed Biphasic Waveform (PBW), the Rectilinear Biphasic Waveform (RBW), and the "lossless" constant current (LLCC) pulses. Two indices are introduced: 1) kf = W/W0 - the ratio between the delivered energy W and the energy W0 of a rectangular pulse with the same duration and electric charge; 2) ηC = W/WC0 - the level of utilizing the initially loaded capacitor energy WC0. The envisioned comparative study shows tha...

  2. The standard biphasic-contrast examination of the stomach and duodenum

    International Nuclear Information System (INIS)

    A standard examination has been developed, called biphasic, because it combines the advantages of positive-contrast and double-contrast techniques. The theoretical background and technique of this examination are described and the basic interpretation of double-contrast studies stated. General remarks on the results and on the complementary role of radiological examination and endoscopy are included. A quantitative study of standard biphasic-contrast examinations in patients over a period of 3 years is presented. Finally a radiological atlas of common lesions of the stomach and duodenum is given. (C.F.)

  3. Development of Ca2+ hotspots between Lymnaea neurons during synaptogenesis.

    Science.gov (United States)

    Feng, Zhong-Ping; Grigoriev, Nikita; Munno, David; Lukowiak, Ken; MacVicar, Brian A; Goldberg, Jeffrey I; Syed, Naweed I

    2002-02-15

    Calcium (Ca2+) channel clustering at specific presynaptic sites is a hallmark of mature synapses. However, the spatial distribution patterns of Ca2+ channels at newly formed synapses have not yet been demonstrated. Similarly, it is unclear whether Ca2+ 'hotspots' often observed at the presynaptic sites are indeed target cell contact specific and represent a specialized mechanism by which Ca2+ channels are targeted to select synaptic sites. Utilizing both soma-soma paired (synapsed) and single neurons from the mollusk Lymnaea, we have tested the hypothesis that differential gradients of voltage-dependent Ca2+ signals develop in presynaptic neuron at its contact point with the postsynaptic neuron; and that these Ca2+ hotspots are target cell contact specific. Fura-2 imaging, or two-photon laser scanning microscopy of Calcium Green, was coupled with electrophysiological techniques to demonstrate that voltage-induced Ca2+ gradients (hotspots) develop in the presynaptic cell at its contact point with the postsynaptic neuron, but not in unpaired single cells. The incidence of Ca2+ hotspots coincided with the appearance of synaptic transmission between the paired cells, and these gradients were target cell contact specific. In contrast, the voltage-induced Ca2+ signal in unpaired neurons was uniformly distributed throughout the somata; a similar pattern of Ca2+ gradient was observed in the presynaptic neuron when it was soma-soma paired with a non-synaptic partner cell. Moreover, voltage clamp recording techniques, in conjunction with a fast, optical differential perfusion system, were used to demonstrate that the total whole-cell Ca2+ (or Ba2+) current density in single and paired cells was not significantly different. However, the amplitude of Ba2+ current was significantly higher in the presynaptic cell at its contact side with the postsynaptic neurons, compared with non-contacted regions. In summary, this study demonstrates that voltage-induced Ca2+ hotspots develop

  4. Structural elements that underlie Doc2β function during asynchronous synaptic transmission.

    Science.gov (United States)

    Xue, Renhao; Gaffaney, Jon D; Chapman, Edwin R

    2015-08-01

    Double C2-like domain-containing proteins alpha and beta (Doc2α and Doc2β) are tandem C2-domain proteins proposed to function as Ca(2+) sensors for asynchronous neurotransmitter release. Here, we systematically analyze each of the negatively charged residues that mediate binding of Ca(2+) to the β isoform. The Ca(2+) ligands in the C2A domain were dispensable for Ca(2+)-dependent translocation to the plasma membrane, with one exception: neutralization of D220 resulted in constitutive translocation. In contrast, three of the five Ca(2+) ligands in the C2B domain are required for translocation. Importantly, translocation was correlated with the ability of the mutants to enhance asynchronous release when overexpressed in neurons. Finally, replacement of specific Ca(2+)/lipid-binding loops of synaptotagmin 1, a Ca(2+) sensor for synchronous release, with corresponding loops from Doc2β, resulted in chimeras that yielded slower kinetics in vitro and slower excitatory postsynaptic current decays in neurons. Together, these data reveal the key determinants of Doc2β that underlie its function during the slow phase of synaptic transmission. PMID:26195798

  5. Synaptic devices based on purely electronic memristors

    Energy Technology Data Exchange (ETDEWEB)

    Pan, Ruobing [Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo 315201 (China); Institute of Materials Science, School of Materials Science and Engineering, Shanghai University, Shanghai 200072 (China); Li, Jun; Zhuge, Fei, E-mail: zhugefei@nimte.ac.cn, E-mail: h-cao@nimte.ac.cn; Zhu, Liqiang; Liang, Lingyan; Zhang, Hongliang; Gao, Junhua; Cao, Hongtao, E-mail: zhugefei@nimte.ac.cn, E-mail: h-cao@nimte.ac.cn; Fu, Bing; Li, Kang [Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo 315201 (China)

    2016-01-04

    Memristive devices have been widely employed to emulate biological synaptic behavior. In these cases, the memristive switching generally originates from electrical field induced ion migration or Joule heating induced phase change. In this letter, the Ti/ZnO/Pt structure was found to show memristive switching ascribed to a carrier trapping/detrapping of the trap sites (e.g., oxygen vacancies or zinc interstitials) in ZnO. The carrier trapping/detrapping level can be controllably adjusted by regulating the current compliance level or voltage amplitude. Multi-level conductance states can, therefore, be realized in such memristive device. The spike-timing-dependent plasticity, an important Hebbian learning rule, has been implemented in this type of synaptic device. Compared with filamentary-type memristive devices, purely electronic memristors have potential to reduce their energy consumption and work more stably and reliably, since no structural distortion occurs.

  6. Synaptic devices based on purely electronic memristors

    Science.gov (United States)

    Pan, Ruobing; Li, Jun; Zhuge, Fei; Zhu, Liqiang; Liang, Lingyan; Zhang, Hongliang; Gao, Junhua; Cao, Hongtao; Fu, Bing; Li, Kang

    2016-01-01

    Memristive devices have been widely employed to emulate biological synaptic behavior. In these cases, the memristive switching generally originates from electrical field induced ion migration or Joule heating induced phase change. In this letter, the Ti/ZnO/Pt structure was found to show memristive switching ascribed to a carrier trapping/detrapping of the trap sites (e.g., oxygen vacancies or zinc interstitials) in ZnO. The carrier trapping/detrapping level can be controllably adjusted by regulating the current compliance level or voltage amplitude. Multi-level conductance states can, therefore, be realized in such memristive device. The spike-timing-dependent plasticity, an important Hebbian learning rule, has been implemented in this type of synaptic device. Compared with filamentary-type memristive devices, purely electronic memristors have potential to reduce their energy consumption and work more stably and reliably, since no structural distortion occurs.

  7. Filamentary Switching: Synaptic Plasticity through Device Volatility

    CERN Document Server

    La Barbera, Selina; Alibart, Fabien

    2015-01-01

    Replicating the computational functionalities and performances of the brain remains one of the biggest challenges for the future of information and communication technologies. Such an ambitious goal requires research efforts from the architecture level to the basic device level (i.e., investigating the opportunities offered by emerging nanotechnologies to build such systems). Nanodevices, or, more precisely, memory or memristive devices, have been proposed for the implementation of synaptic functions, offering the required features and integration in a single component. In this paper, we demonstrate that the basic physics involved in the filamentary switching of electrochemical metallization cells can reproduce important biological synaptic functions that are key mechanisms for information processing and storage. The transition from short- to long-term plasticity has been reported as a direct consequence of filament growth (i.e., increased conductance) in filamentary memory devices. In this paper, we show tha...

  8. Cellular and synaptic network defects in autism

    OpenAIRE

    Peça, João; Feng, Guoping

    2012-01-01

    Many candidate genes are now thought to confer susceptibility to autism spectrum disorders (ASDs). Here we review four interrelated complexes, each composed of multiple families of genes that functionally coalesce on common cellular pathways. We illustrate a common thread in the organization of glutamatergic synapses and suggest a link between genes involved in Tuberous Sclerosis Complex, Fragile X syndrome, Angelman syndrome and several synaptic ASD candidate genes. When viewed in this conte...

  9. Retinal synaptic regeneration via microfluidic guiding channels

    OpenAIRE

    Ping-Jung Su; Zongbin Liu; Kai Zhang; Xin Han; Yuki Saito; Xiaojun Xia; Kenji Yokoi; Haifa Shen; Lidong Qin

    2015-01-01

    In vitro culture of dissociated retinal neurons is an important model for investigating retinal synaptic regeneration (RSR) and exploring potentials in artificial retina. Here, retinal precursor cells were cultured in a microfluidic chip with multiple arrays of microchannels in order to reconstruct the retinal neuronal synapse. The cultured retinal cells were physically connected through microchannels. Activation of electric signal transduction by the cells through the microchannels was demon...

  10. Morphological plasticity of astroglia: Understanding synaptic microenvironment

    OpenAIRE

    Heller, J. P.; Rusakov, D. A.

    2015-01-01

    Memory formation in the brain is thought to rely on the remodeling of synaptic connections which eventually results in neural network rewiring. This remodeling is likely to involve ultrathin astroglial protrusions which often occur in the immediate vicinity of excitatory synapses. The phenomenology, cellular mechanisms, and causal relationships of such astroglial restructuring remain, however, poorly understood. This is in large part because monitoring and probing of the underpinning molecula...

  11. Cationic influences upon synaptic transmission at the hair cell-afferent fiber synapse of the frog

    Science.gov (United States)

    Cochran, S. L.

    1995-01-01

    The concentrations of inorganic cations (K+, Na+, and Ca2+) bathing the isolated frog labyrinth were varied in order to assess their role in influencing and mediating synaptic transmission at the hair cell-afferent fiber synapse. Experiments employed intracellular recordings of synaptic activity from VIIIth nerve afferents. Recordings were digitized continuously at 50 kHz, and excitatory postsynaptic potentials were detected and parameters quantified by computer algorithms. Particular attention was focused on cationic effects upon excitatory postsynaptic potential frequency of occurrence and excitatory postsynaptic potential amplitude, in order to discriminate between pre- and postsynaptic actions. Because the small size of afferents preclude long term stable recordings, alterations in cationic concentrations were applied transiently and their peak effects on synaptic activity were assessed. Increases in extracellular K+ concentration of a few millimolar produced a large increase in the frequency of occurrence of excitatory postsynaptic potentials with little change in amplitude, indicating that release of transmitter from the hair cell is tightly coupled to its membrane potential. Increasing extracellular Na+ concentration resulted in an increase in excitatory postsynaptic potential amplitude with no significant change in excitatory postsynaptic potential frequency of occurrence, suggesting that the transmitter-gated subsynaptic channel conducts Na+ ions. Decreases in extracellular Ca2+ concentration had little effect upon excitatory postsynaptic potential frequency, but increased excitatory postsynaptic potential frequency and amplitude. These findings suggest that at higher concentrations Ca2+ act presynaptically to prevent transmitter release and postsynaptically to prevent Na+ influx during the generation of the excitatory postsynaptic potential. The influences of these ions on synaptic activity at this synapse are remarkably similar to those reported at the

  12. Phase dependent sign changes of GABAergic synaptic input explored in-silicio and in-vitro.

    Science.gov (United States)

    Stiefel, Klaus M; Wespatat, Valérie; Gutkin, Boris; Tennigkeit, Frank; Singer, Wolf

    2005-08-01

    Inhibitory interactions play a crucial role in the synchronization of neuronal activity. Here we investigate the effect of GABAergic PSPs on spike timing in cortical neurons that exhibit an oscillatory modulation of their membrane potential. To this end we combined numerical simulations with in-vitro patch-clamp recordings from layer II/III pyramidal cells of the rat visual cortex. Special emphasis was placed on exploring how the reversal potential of the GABAergic synaptic currents (EGABA) and the phase relations of the PSPs relative to the oscillation cycles affect the timing of spikes riding on the depolarizing peaks of the oscillations. The simulations predicted: (1) With EGABA more negative than the oscillation minima PSPs are hyperpolarizing at all phases and thus delay or prevent spikes. (2) With EGABA being more positive than the oscillation maxima PSPs are depolarizing in a phase-independent way and lead to a phase advance of spikes. (3) In the intermediate case where EGABA lies within oscillation maxima and minima PSPs are either hyper- or depolarizing depending on their phase relations to the V(m) oscillations and can therefore either delay or advance spikes. Experiments conducted in this most interesting last configuration with biphasic PSPs agreed with the model predictions. Additional theoretical investigations revealed the effect of these PSP induced shifts in spike timing on synchronization in neuronal circuits. The results suggest that GABAergic mechanisms can assume highly specific timing functions in oscillatory networks.

  13. Synaptic theory of Replicator-like melioration

    Directory of Open Access Journals (Sweden)

    Yonatan Loewenstein

    2010-06-01

    Full Text Available According to the theory of Melioration, organisms in repeated choice settings shift their choice preference in favor of the alternative that provides the highest return. The goal of this paper is to explain how this learning behavior can emerge from microscopic changes in the efficacies of synapses, in the context of two-alternative repeated-choice experiment. I consider a large family of synaptic plasticity rules in which changes in synaptic efficacies are driven by the covariance between reward and neural activity. I construct a general framework that predicts the learning dynamics of any decision-making neural network that implements this synaptic plasticity rule and show that melioration naturally emerges in such networks. Moreover, the resultant learning dynamics follows the Replicator equation which is commonly used to phenomenologically describe changes in behavior in operant conditioning experiments. Several examples demonstrate how the learning rate of the network is affected by its properties and by the specifics of the plasticity rule. These results help bridge the gap between cellular physiology and learning behavior.

  14. Characterization and extraction of the synaptic apposition surface for synaptic geometry analysis

    Science.gov (United States)

    Morales, Juan; Rodríguez, Angel; Rodríguez, José-Rodrigo; DeFelipe, Javier; Merchán-Pérez, Angel

    2013-01-01

    Geometrical features of chemical synapses are relevant to their function. Two critical components of the synaptic junction are the active zone (AZ) and the postsynaptic density (PSD), as they are related to the probability of synaptic release and the number of postsynaptic receptors, respectively. Morphological studies of these structures are greatly facilitated by the use of recent electron microscopy techniques, such as combined focused ion beam milling and scanning electron microscopy (FIB/SEM), and software tools that permit reconstruction of large numbers of synapses in three dimensions. Since the AZ and the PSD are in close apposition and have a similar surface area, they can be represented by a single surface—the synaptic apposition surface (SAS). We have developed an efficient computational technique to automatically extract this surface from synaptic junctions that have previously been three-dimensionally reconstructed from actual tissue samples imaged by automated FIB/SEM. Given its relationship with the release probability and the number of postsynaptic receptors, the surface area of the SAS is a functionally relevant measure of the size of a synapse that can complement other geometrical features like the volume of the reconstructed synaptic junction, the equivalent ellipsoid size and the Feret's diameter. PMID:23847474

  15. Biphasic Alteration of the Inhibitory Synapse Scaffold Protein Gephyrin in Early and Late Stages of an Alzheimer Disease Model.

    Science.gov (United States)

    Kiss, Eva; Gorgas, Karin; Schlicksupp, Andrea; Groß, Dagmar; Kins, Stefan; Kirsch, Joachim; Kuhse, Jochen

    2016-09-01

    The pathogenesis of Alzheimer disease (AD) is thought to begin many years before the diagnosis of dementia. Accumulating evidence indicates the involvement of GABAergic neurotransmission in the physiopathology of AD. However, in comparison to excitatory synapses, the structural and functional alterations of inhibitory synapses in AD are less well characterized. We studied the expression and distribution of proteins specific for inhibitory synapses in hippocampal areas of APPPS1 mice at different ages. Interestingly, by immunoblotting and confocal fluorescence microscopy, we disclosed a robust increase in the expression of gephyrin, an organizer of ligand-gated ion channels at inhibitory synapses in hippocampus CA1 and dentate gyrus of young presymptomatic APPPS1 mice (1 to 3 months) as compared to controls. The postsynaptic γ2-GABA(A)-receptor subunit and the presynaptic vesicular inhibitory amino acid transporter protein showed similar expression patterns. In contrast, adult transgenic animals (12 months) displayed decreased levels of these proteins in comparison to wild type in hippocampus areas devoid of amyloid plaques. Within most plaques, strong gephyrin immunoreactivity was detected, partially colocalizing with vesicular amino acid transporter and GABA(A)-receptor γ2 subunit immunoreactivities. Our results indicate a biphasic alteration in expression of hippocampal inhibitory synapse components in AD. Altered inhibition of neurotransmission might be an early prognostic marker and might even be involved in the pathogenesis of AD.

  16. Biphasic Alteration of the Inhibitory Synapse Scaffold Protein Gephyrin in Early and Late Stages of an Alzheimer Disease Model.

    Science.gov (United States)

    Kiss, Eva; Gorgas, Karin; Schlicksupp, Andrea; Groß, Dagmar; Kins, Stefan; Kirsch, Joachim; Kuhse, Jochen

    2016-09-01

    The pathogenesis of Alzheimer disease (AD) is thought to begin many years before the diagnosis of dementia. Accumulating evidence indicates the involvement of GABAergic neurotransmission in the physiopathology of AD. However, in comparison to excitatory synapses, the structural and functional alterations of inhibitory synapses in AD are less well characterized. We studied the expression and distribution of proteins specific for inhibitory synapses in hippocampal areas of APPPS1 mice at different ages. Interestingly, by immunoblotting and confocal fluorescence microscopy, we disclosed a robust increase in the expression of gephyrin, an organizer of ligand-gated ion channels at inhibitory synapses in hippocampus CA1 and dentate gyrus of young presymptomatic APPPS1 mice (1 to 3 months) as compared to controls. The postsynaptic γ2-GABA(A)-receptor subunit and the presynaptic vesicular inhibitory amino acid transporter protein showed similar expression patterns. In contrast, adult transgenic animals (12 months) displayed decreased levels of these proteins in comparison to wild type in hippocampus areas devoid of amyloid plaques. Within most plaques, strong gephyrin immunoreactivity was detected, partially colocalizing with vesicular amino acid transporter and GABA(A)-receptor γ2 subunit immunoreactivities. Our results indicate a biphasic alteration in expression of hippocampal inhibitory synapse components in AD. Altered inhibition of neurotransmission might be an early prognostic marker and might even be involved in the pathogenesis of AD. PMID:27423698

  17. Improving the extraction and purification of immunoglobulin G by the use of ionic liquids as adjuvants in aqueous biphasic systems.

    Science.gov (United States)

    Ferreira, Ana M; Faustino, Vânia F M; Mondal, Dibyendu; Coutinho, João A P; Freire, Mara G

    2016-10-20

    Immunoglobulins G (IgG) could become widespread biopharmaceuticals if cost-efficient processes for their extraction and purification are available. In this work, aqueous biphasic systems (ABS) composed of polyethylene glycols and a buffered salt, and with ionic liquids (ILs) as adjuvants, have been studied as alternative extraction and purification platforms of IgG from a rabbit serum source. Eleven ILs were investigated to provide insights on the chemical features which maximize the IgG partitioning. It is shown that in polymer-salt systems pure IgG preferentially partitions to the polymer-rich phase; yet, the complete extraction was never attained. Remarkably, after the addition of 5wt% of adequate ILs to polymer-salt ABS, the complete extraction of pure IgG in a single-step was accomplished. The best systems and conditions were then applied to the extraction and purification of IgG directly from rabbit serum samples. The complete extraction of IgG in a single-step was maintained while its purity in the polymer-rich phase was enhanced by ca. 37% as compared to the IL-free ABS. The antibody stability was also evaluated revealing that appropriate ILs are able to maintain the IgG stability and can be used as phase-forming components of ABS when envisaging the purification of high-cost biopharmaceuticals.

  18. Synthesis and characterization of porous biphasic calcium phosphate scaffold from different porogens for possible bone tissue engineering applications

    Directory of Open Access Journals (Sweden)

    Amera A.

    2011-01-01

    Full Text Available By using the wet precipitation method, Biphasic calcium phosphate granules were synthesized with Ca/P ratio1.52 and controlled porosity, pore size distribution, and granule size. Microporosity was then obtained by adjusting sintering temperature while macroporosity was prepared by adding 1:3 wt% ratio of two normally used porogens (naphthalene and sugar and 2 newly introduced porogens (sago and lentil. Samples from each ratio were pressed into pellets and were fired at 500ºC for 2 hours with 0.5°C/minute heating rate (for removal of porogens and further sintered at 850°C for 2 hours with 5°C/minute before cooling down to room temperature. The granules were prepared by crushing and sieving BCP sintered pellets to get granules of sizes ranging from 250-500μm. X-rays diffraction (XRD, field emission scanning electron microscope (FESEM, particle size and porosity analyses were employed in order to characterize the granules. A round to oval shape pores with 200-400 μm size were obtained and identical to the prepared porogens’ particle size. This approach gives the desirable properties near to normal bone leading to a perfect osteogenesis for the purpose tissue engineering.

  19. Triple-channel microreactor for biphasic gas–liquid reactions: Photosensitized oxygenations

    Directory of Open Access Journals (Sweden)

    Ram Awatar Maurya

    2011-08-01

    Full Text Available A triple-channel microreactor fabricated by means of a soft-lithography technique was devised for efficient biphasic gas–liquid reactions. The excellent performance of the microreactor was demonstrated by carrying out photosensitized oxygenations of α-terpinene, citronellol, and allyl alcohols.

  20. Triple-channel microreactor for biphasic gas–liquid reactions: Photosensitized oxygenations

    OpenAIRE

    Ram Awatar Maurya; Chan Pil Park; Dong-Pyo Kim

    2011-01-01

    A triple-channel microreactor fabricated by means of a soft-lithography technique was devised for efficient biphasic gas–liquid reactions. The excellent performance of the microreactor was demonstrated by carrying out photosensitized oxygenations of α-terpinene, citronellol, and allyl alcohols.

  1. Calculation of the valence electron structures of alloying cementite and its biphase interface

    Institute of Scientific and Technical Information of China (English)

    刘志林; 李志林; 刘伟东

    2001-01-01

    The valence electron structures of alloying cementite θ-(Fe, M)3C and ε-(Fe, M)3C andthose of the biphase interfaces between them and α-Fe are calculated with Yu's empirical electrontheory of solid and molecules. The calculation results accord with the actual behavior of alloys.

  2. Phase Behaviors in Bi-phase Simulation of Powder Segregation in Metal Injection Molding

    Institute of Scientific and Technical Information of China (English)

    Liu Baosheng; Fan Xiaoxin; Cheng Zhiqiang

    2006-01-01

    Powder segregation induced by mold filling is an important phenomenon that affects the final quality of metal injection molding (MIM). The prediction of segregation in MIM requires a bi-phase flow model to describe distinctly the flows of metallic powder and polymer binder. Viscous behaviors for the flows of each phase should hence be determined. The coefficient of interaction between the flows of two phases should also be evaluated. However, only viscosity of the mixed feedstock is measurable by capillary tests. Wall sticking is supposed in the traditional model for capillary tests, while the wall slip is important to be taken into account in MIM injection. Objective of the present paper is to introduce the slip effect in bi-phase simulation, and search the suitable way to determine the viscous behaviors for each phase with the consideration of wall slip in capillary tests. Analytical and numerical methods were proposed to realize such a specific purpose. The proposed method is based on the mass conservation between the capillary flows in mono-phase model for the mixed feedstock and in bi-phase model for the flows of two phases. Examples of the bi-phase simulation in MIM were realized with the software developed by research team. The results show evident segregation, which is valuable for improving the mould designs.

  3. Biphasic Catalytic(Hydroformylation of 1-Dodecene in Micellar System with Cationic Gemini Surfactants

    Institute of Scientific and Technical Information of China (English)

    Min LI; Bin XU; Hua CHEN; Hong Jie ZHENG; Xue Yuan HUANG; Yao Zhong LI; Xian Jun LI

    2004-01-01

    The promotion effect of cationic gemini surfactants for the hydroformylation of 1-dodecene in the organic/aqueous biphasic catalytic system is reported. The hydroformylation reaction in the presence of gemini surfactant occurred with higher turnover frequency and higher selectivity for linear aldehyde than using conventional monomeric surfactant CTAB.

  4. Biphasic electrical field stimulation aids in tissue engineering of multicell-type cardiac organoids.

    Science.gov (United States)

    Chiu, Loraine L Y; Iyer, Rohin K; King, John-Paul; Radisic, Milica

    2011-06-01

    The main objectives of current work were (1) to compare the effects of monophasic or biphasic electrical field stimulation on structure and function of engineered cardiac organoids based on enriched cardiomyocytes (CM) and (2) to determine if electrical field stimulation will enhance electrical excitability of cardiac organoids based on multiple cell types. Organoids resembling cardiac myofibers were cultivated in Matrigel-coated microchannels fabricated of poly(ethylene glycol)-diacrylate. We found that field stimulation using symmetric biphasic square pulses at 2.5 V/cm, 1 Hz, 1 ms (per pulse phase) was an improved stimulation protocol, as compared to no stimulation and stimulation using monophasic square pulses of identical total amplitude and duration (5 V/cm, 1 Hz, 2 ms). This was supported by the highest success rate for synchronous contractions, low excitation threshold, the highest cell density, and the highest expression of Connexin-43 in the biphasic group. Subsequently, enriched CM were seeded on the networks of (1) cardiac fibroblasts (FB), (2) D4T endothelial cells (EC), or (3) a mixture of FB and EC that were precultured for 2 days prior to the addition of enriched CM. Biphasic field stimulation was also effective at improving electrical excitability of these cardiac organoids by improving the three-dimensional organization of the cells, increasing cellular elongation and enhancing Connexin-43 presence.

  5. A New Type of Biphasic Calcium Phosphate Cement as a Gentamicin Carrier for Osteomyelitis

    Directory of Open Access Journals (Sweden)

    Wen-Yu Su

    2013-01-01

    Full Text Available Osteomyelitis therapy is a long-term and inconvenient procedure for a patient. Antibiotic-loaded bone cements are both a complementary and alternative treatment option to intravenous antibiotic therapy for the treatment of osteomyelitis. In the current study, the biphasic calcium phosphate cement (CPC, called α-TCP/HAP (α-tricalcium phosphate/hydroxyapatite biphasic cement, was prepared as an antibiotics carrier for osteomyelitis. The developed biphasic cement with a microstructure of α-TCP surrounding the HAP has a fast setting time which will fulfill the clinical demand. The X-ray diffraction and Fourier transform infrared spectrometry analyses showed the final phase to be HAP, the basic bone mineral, after setting for a period of time. Scanning electron microscopy revealed a porous structure with particle sizes of a few micrometers. The addition of gentamicin in α-TCP/HAP would delay the transition of α-TCP but would not change the final-phase HAP. The gentamicin-loaded α-TCP/HAP supplies high doses of the antibiotic during the initial 24 hours when they are soaked in phosphate buffer solution (PBS. Thereafter, a slower drug release is produced, supplying minimum inhibitory concentration until the end of the experiment (30 days. Studies of growth inhibition of Staphylococcus aureus and Pseudomonas aeruginosa in culture indicated that gentamicin released after 30 days from α-TCP/HAP biphasic cement retained antibacterial activity.

  6. A role for Mints in transmitter release: Mint 1 knockout mice exhibit impaired GABAergic synaptic transmission

    OpenAIRE

    Ho, Angela; Morishita, Wade; Hammer, Robert E.; Malenka, Robert C.; Südhof, Thomas C.

    2003-01-01

    Mints (also called X11-like proteins) are adaptor proteins composed of divergent N-terminal sequences that bind to synaptic proteins such as CASK (Mint 1 only) and Munc18-1 (Mints 1 and 2) and conserved C-terminal PTB- and PDZ-domains that bind to widely distributed proteins such as APP, presenilins, and Ca2+ channels (all Mints). We find that Mints 1 and 2 are similarly expressed in most neurons except for inhibitory interneurons that contain selectively high levels of Mint 1. Using knockout...

  7. Velocity dependence of biphasic flow structuration: steady-state and oscillating flow effects

    Science.gov (United States)

    Tore Tallakstad, Ken; Jankov, Mihailo; Løvoll, Grunde; Toussaint, Renaud; Jørgen Mâløy, Knut; Grude Flekkøy, Eirik; Schmittbuhl, Jean; Schäfer, Gerhard; Méheust, Yves; Arendt Knudsen, Henning

    2010-05-01

    We study various types of biphasic flows in quasi-two-dimensional transparent porous models. These flows imply a viscous wetting fluid, and a lowly viscous one. The models are transparent, allowing the displacement process and structure to be monitored in space and time. Three different aspects will be presented: 1. In stationary biphasic flows, we study the relationship between the macroscopic pressure drop (related to relative permeability) and the average flow rate, and how this arises from the cluster size distribution of the lowly viscous fluid [1]. 2. In drainage situations, we study how the geometry of the invader can be explained, and how it gives rise to apparent dynamic capillary effects. We show how these can be explained by viscous effects on evolving geometries of invading fluid [2]. 3. We study the impact of oscillating pressure fields superimposed to a background flow over the flow regimes patterns [3]. Steady-State Two-Phase Flow in Porous Media: Statistics and Transport Properties. First, in stationary flow with a control of the flux of both fluids, we show how the pressure drop depends on the flow rate. We will show that the dynamics is dominated by the interplay between a viscous pressure field from the wetting fluid and bubble transport of a less viscous, nonwetting phase. In contrast with more studied displacement front systems, steady-state flow is in equilibrium, statistically speaking. The corresponding theoretical simplicity allows us to explain a data collapse in the cluster size distribution of lowly viscous fluid in the system, as well as the relation |?P|∞√Ca--. This allows to explain so called relative permeability effects by the morphological changes of the cluster size distribution. Influence of viscous fingering on dynamic saturation-pressure curves in porous media. Next, we study drainage in such models, and investigate the relationship between the pressure field and the morphology of the invading fluid. This allows to model

  8. Synaptic Contacts Enhance Cell-to-Cell Tau Pathology Propagation

    Directory of Open Access Journals (Sweden)

    Sara Calafate

    2015-05-01

    Full Text Available Accumulation of insoluble Tau protein aggregates and stereotypical propagation of Tau pathology through the brain are common hallmarks of tauopathies, including Alzheimer’s disease (AD. Propagation of Tau pathology appears to occur along connected neurons, but whether synaptic contacts between neurons are facilitating propagation has not been demonstrated. Using quantitative in vitro models, we demonstrate that, in parallel to non-synaptic mechanisms, synapses, but not merely the close distance between the cells, enhance the propagation of Tau pathology between acceptor hippocampal neurons and Tau donor cells. Similarly, in an artificial neuronal network using microfluidic devices, synapses and synaptic activity are promoting neuronal Tau pathology propagation in parallel to the non-synaptic mechanisms. Our work indicates that the physical presence of synaptic contacts between neurons facilitate Tau pathology propagation. These findings can have implications for synaptic repair therapies, which may turn out to have adverse effects by promoting propagation of Tau pathology.

  9. Synaptic Contacts Enhance Cell-to-Cell Tau Pathology Propagation.

    Science.gov (United States)

    Calafate, Sara; Buist, Arjan; Miskiewicz, Katarzyna; Vijayan, Vinoy; Daneels, Guy; de Strooper, Bart; de Wit, Joris; Verstreken, Patrik; Moechars, Diederik

    2015-05-26

    Accumulation of insoluble Tau protein aggregates and stereotypical propagation of Tau pathology through the brain are common hallmarks of tauopathies, including Alzheimer's disease (AD). Propagation of Tau pathology appears to occur along connected neurons, but whether synaptic contacts between neurons are facilitating propagation has not been demonstrated. Using quantitative in vitro models, we demonstrate that, in parallel to non-synaptic mechanisms, synapses, but not merely the close distance between the cells, enhance the propagation of Tau pathology between acceptor hippocampal neurons and Tau donor cells. Similarly, in an artificial neuronal network using microfluidic devices, synapses and synaptic activity are promoting neuronal Tau pathology propagation in parallel to the non-synaptic mechanisms. Our work indicates that the physical presence of synaptic contacts between neurons facilitate Tau pathology propagation. These findings can have implications for synaptic repair therapies, which may turn out to have adverse effects by promoting propagation of Tau pathology.

  10. The impact of synapsins on synaptic plasticity and cognitive behaviors

    Institute of Scientific and Technical Information of China (English)

    Lin ZHANG; Zhong-Xin ZHAO

    2006-01-01

    Synapsins are a family of phosphoproteins specifically associated with the cytoplasmic surface of the synaptic vesicle membrane, appearing to regulate neurotransmitter release, the formation and maintenance of synaptic contacts.They could induce the change of the synaptic plasticity to regulate various adaptation reactions, and change the cognitive behaviors. So we presume that if some cognitive behavior are damaged, synapsins would be changed as well. This gives us a new recognition of better diagnosis and therapy of cognitive disorder desease.

  11. Roles of Synaptic MAGUK Proteins in Analgesia and Anesthesia

    Institute of Scientific and Technical Information of China (English)

    TAO Yuan-xiang

    2004-01-01

    @@ In the central nervous system, synapses, highly specialized sites of contact between neurons, are organized to facilitate the transmission of signals from the pre-synaptic terminal to the postsynaptic membrane and to activate subsequent signal transduction cascades that result in appropriate cellular events. Efficient and precise organization of synaptic proteins such as receptors, ion channels, and signaling molecules at both pre-synaptic and postsynaptic membranes is critical for proper signal transmission.

  12. Synapsin IIa controls the reserve pool of glutamatergic synaptic vesicles

    OpenAIRE

    Gitler, Daniel; Cheng, Qing; Greengard, Paul; Augustine, George J.

    2008-01-01

    Synapsins regulate synaptic transmission by controlling the reserve pool of synaptic vesicles. Each of the three mammalian synapsin genes is subject to alternative splicing, yielding several isoforms whose roles are unknown. To investigate the function of these isoforms, we examined the synaptic effects of introducing each isoform into glutamatergic cultured hippocampal neurons from synapsin triple knock-out mice. Remarkably, we found that synapsin IIa was the only isoform that could rescue t...

  13. Concurrent Imaging of Synaptic Vesicle Recycling and Calcium Dynamics

    OpenAIRE

    Li, Haiyan; Foss, Sarah M.; Dobryy, Yuriy L.; Park, C. Kevin; Hires, Samuel Andrew; Shaner, Nathan C.; Tsien, Roger Y.; Osborne, Leslie C.; Voglmaier, Susan M.

    2011-01-01

    Synaptic transmission involves the calcium dependent release of neurotransmitter from synaptic vesicles. Genetically encoded optical probes emitting different wavelengths of fluorescent light in response to neuronal activity offer a powerful approach to understand the spatial and temporal relationship of calcium dynamics to the release of neurotransmitter in defined neuronal populations. To simultaneously image synaptic vesicle recycling and changes in cytosolic calcium, we developed a red-sh...

  14. Concurrent imaging of synaptic vesicle recycling and calcium dynamics.

    OpenAIRE

    Haiyan eLi; Foss, Sarah M.; Yuriy eDobryy; C. Kevin ePark; Samuel Andrew Hires; Shaner, Nathan C.; Tsien, Roger Y.; Osborne, Leslie C.; Voglmaier, Susan M.

    2011-01-01

    Synaptic transmission involves the calcium-dependent release of neurotransmitter from synaptic vesicles. Genetically encoded optical probes emitting different wavelengths of fluorescent light in response to neuronal activity offer a powerful approach to understand the spatial and temporal relationship of calcium dynamics to the release of neurotransmitter in defined neuronal populations. To simultaneously image synaptic vesicle recycling and changes in cytosolic calcium, we developed a red-...

  15. Restoration of synaptic function in sight for degenerative retinal disease

    OpenAIRE

    Schubert, Timm; Wissinger, Bernd

    2015-01-01

    Synaptic disorganization is a prominent feature of many neurological diseases of the CNS, including Parkinson’s disease, intellectual development disorders, and autism. Although synaptic plasticity is critical for learning and memory, it is unclear whether this innate property helps restore synaptic function in disease once the primary cause of disease is abrogated. An answer to this question may come from a recent investigation in X-linked retinoschisis, a currently untreatable retinopathy. ...

  16. A Voltage Mode Memristor Bridge Synaptic Circuit with Memristor Emulators

    OpenAIRE

    Leon Chua; Maheshwar Pd. Sah; Hyongsuk Kim; Changju Yang

    2012-01-01

    A memristor bridge neural circuit which is able to perform signed synaptic weighting was proposed in our previous study, where the synaptic operation was verified via software simulation of the mathematical model of the HP memristor. This study is an extension of the previous work advancing toward the circuit implementation where the architecture of the memristor bridge synapse is built with memristor emulator circuits. In addition, a simple neural network which performs both synaptic weighti...

  17. Neuroligins and Neurexins Link Synaptic Function to Cognitive Disease

    OpenAIRE

    Südhof, Thomas C.

    2008-01-01

    The brain processes information by transmitting signals at synapses, which connect neurons into vast networks of communicating cells. In these networks, synapses not only transmit, but also process and refine information. Neurexins and neuroligins are synaptic cell-adhesion molecules that connect pre- and postsynaptic neurons at synapses, mediate trans-synaptic signaling, and shape neural network properties by specifying synaptic functions. In humans, alterations in neurexin or neuroligin gen...

  18. Emotional enhancement of memory: how norepinephrine enables synaptic plasticity

    OpenAIRE

    Tully Keith; Bolshakov Vadim Y

    2010-01-01

    Abstract Changes in synaptic strength are believed to underlie learning and memory. We explore the idea that norepinephrine is an essential modulator of memory through its ability to regulate synaptic mechanisms. Emotional arousal leads to activation of the locus coeruleus with the subsequent release of norepineprine in the brain, resulting in the enhancement of memory. Norepinephrine activates both pre- and post-synaptic adrenergic receptors at central synapses with different functional outc...

  19. Distinct Functions of Endophilin Isoforms in Synaptic Vesicle Endocytosis

    Directory of Open Access Journals (Sweden)

    Jifeng Zhang

    2015-01-01

    Full Text Available Endophilin isoforms perform distinct characteristics in their interactions with N-type Ca2+ channels and dynamin. However, precise functional differences for the endophilin isoforms on synaptic vesicle (SV endocytosis remain unknown. By coupling RNA interference and electrophysiological recording techniques in cultured rat hippocampal neurons, we investigated the functional differences of three isoforms of endophilin in SV endocytosis. The results showed that the amplitude of normalized evoked excitatory postsynaptic currents in endophilin1 knockdown neurons decreased significantly for both single train and multiple train stimulations. Similar results were found using endophilin2 knockdown neurons, whereas endophilin3 siRNA exhibited no change compared with control neurons. Endophilin1 and endophilin2 affected SV endocytosis, but the effect of endophilin1 and endophilin2 double knockdown was not different from that of either knockdown alone. This result suggested that endophilin1 and endophilin2 functioned together but not independently during SV endocytosis. Taken together, our results indicate that SV endocytosis is sustained by endophilin1 and endophilin2 isoforms, but not by endophilin3, in primary cultured hippocampal neurons.

  20. Asymmetry of Neuronal Combinatorial Codes Arises from Minimizing Synaptic Weight Change.

    Science.gov (United States)

    Leibold, Christian; Monsalve-Mercado, Mauro M

    2016-08-01

    Synaptic change is a costly resource, particularly for brain structures that have a high demand of synaptic plasticity. For example, building memories of object positions requires efficient use of plasticity resources since objects can easily change their location in space and yet we can memorize object locations. But how should a neural circuit ideally be set up to integrate two input streams (object location and identity) in case the overall synaptic changes should be minimized during ongoing learning? This letter provides a theoretical framework on how the two input pathways should ideally be specified. Generally the model predicts that the information-rich pathway should be plastic and encoded sparsely, whereas the pathway conveying less information should be encoded densely and undergo learning only if a neuronal representation of a novel object has to be established. As an example, we consider hippocampal area CA1, which combines place and object information. The model thereby provides a normative account of hippocampal rate remapping, that is, modulations of place field activity by changes of local cues. It may as well be applicable to other brain areas (such as neocortical layer V) that learn combinatorial codes from multiple input streams. PMID:27348595

  1. UBE3A Regulates Synaptic Plasticity and Learning and Memory by Controlling SK2 Channel Endocytosis

    Directory of Open Access Journals (Sweden)

    Jiandong Sun

    2015-07-01

    Full Text Available Gated solely by activity-induced changes in intracellular calcium, small-conductance potassium channels (SKs are critical for a variety of functions in the CNS, from learning and memory to rhythmic activity and sleep. While there is a wealth of information on SK2 gating, kinetics, and Ca2+ sensitivity, little is known regarding the regulation of SK2 subcellular localization. We report here that synaptic SK2 levels are regulated by the E3 ubiquitin ligase UBE3A, whose deficiency results in Angelman syndrome and overexpression in increased risk of autistic spectrum disorder. UBE3A directly ubiquitinates SK2 in the C-terminal domain, which facilitates endocytosis. In UBE3A-deficient mice, increased postsynaptic SK2 levels result in decreased NMDA receptor activation, thereby impairing hippocampal long-term synaptic plasticity. Impairments in both synaptic plasticity and fear conditioning memory in UBE3A-deficient mice are significantly ameliorated by blocking SK2. These results elucidate a mechanism by which UBE3A directly influences cognitive function.

  2. Mind Bomb-2 Regulates Hippocampus-dependent Memory Formation and Synaptic Plasticity.

    Science.gov (United States)

    Kim, Somi; Kim, TaeHyun; Lee, Hye-Ryeon; Kong, Young-Yun; Kaang, Bong-Kiun

    2015-11-01

    Notch signaling is a key regulator of neuronal fate during embryonic development, but its function in the adult brain is still largely unknown. Mind bomb-2 (Mib2) is an essential positive regulator of the Notch pathway, which acts in the Notch signal-sending cells. Therefore, genetic deletion of Mib2 in the mouse brain might help understand Notch signaling-mediated cell-cell interactions between neurons and their physiological function. Here we show that deletion of Mib2 in the mouse brain results in impaired hippocampal spatial memory and contextual fear memory. Accordingly, we found impaired hippocampal synaptic plasticity in Mib2 knock-out (KO) mice; however, basal synaptic transmission did not change at the Schaffer collateral-CA1 synapses. Using western blot analysis, we found that the level of cleaved Notch1 was lower in Mib2 KO mice than in wild type (WT) littermates after mild foot shock. Taken together, these data suggest that Mib2 plays a critical role in synaptic plasticity and spatial memory through the Notch signaling pathway.

  3. Measurement of quantal secretion induced by ouabain and its correlation with depletion of synaptic vesicles.

    Science.gov (United States)

    Haimann, C; Torri-Tarelli, F; Fesce, R; Ceccarelli, B

    1985-11-01

    Ouabain (0.1 and 0.05 mM) was applied to frog cutaneous pectoris nerve-muscle preparations bathed in modified Ringer's solution containing either 1.8 mM Ca2+ (and 4 mM Mg2+) or no added Ca2+ (4 mM Mg2+ and 1 mM EGTA). During the intense quantal release of acetylcholine (ACh) induced by ouabain, the parameters of the miniature endplate potentials (mepps) were deduced from the variance, skew, and power spectra of the endplate recordings by applying a recently described modification of classical fluctuation analysis. Often the high frequency of mepps is not stationary; therefore, the signal was high-pass filtered (time constant of the resistance-capacitance filter of 2 ms) to remove the errors introduced by nonstationarity. When ouabain was applied in the presence of Ca2+, mepp frequency started to rise exponentially after a lag of 1.5-2 h, reached an average peak frequency of 1,300/s in approximately 30 min, and then suddenly subsided to low level (10/s). In Ca2+-free solution, after a shorter lag (1-1.5 h), mepp frequency rose to peak rate of 700/s in approximately 20 min and then gradually subsided. In spite of the different time course of secretion in the two experimental conditions, the cumulative quantal release was not significantly different (7.4 +/- 1.3 X 10(5) in Ca2+-containing and 8.8 +/- 2.7 X 10(5) in Ca2+-free solutions). 60 min after the peak secretion, the muscles were fixed for observation in the electron microscope. Morphometric analysis on micrographs of neuromuscular junctions revealed in both cases a profound depletion of synaptic vesicles and deep infoldings of presynaptic membrane. This rapid depletion and the lack of uptake of horseradish peroxidase suggest that ouabain impairs the recycling process that tends to conserve the vesicle population during intense secretion of neurotransmitter. The good correlation observed between the reduction in the store of synaptic vesicles and the total number of quanta of ACh secreted in the absence of a

  4. Intense synaptic activity enhances temporal resolution in spinal motoneurons

    DEFF Research Database (Denmark)

    Berg, Rune W; Ditlevsen, Susanne; Hounsgaard, Jørn Dybkjær

    2008-01-01

    In neurons, spike timing is determined by integration of synaptic potentials in delicate concert with intrinsic properties. Although the integration time is functionally crucial, it remains elusive during network activity. While mechanisms of rapid processing are well documented in sensory systems......, agility in motor systems has received little attention. Here we analyze how intense synaptic activity affects integration time in spinal motoneurons during functional motor activity and report a 10-fold decrease. As a result, action potentials can only be predicted from the membrane potential within 10 ms...... and excitatory synaptic activity. By shortening the effective integration time, this intense synaptic input may serve to facilitate the generation of rapid changes in movements....

  5. Experimental Implementation of a Biometric Laser Synaptic Sensor

    Directory of Open Access Journals (Sweden)

    Alexander N. Pisarchik

    2013-12-01

    Full Text Available We fabricate a biometric laser fiber synaptic sensor to transmit information from one neuron cell to the other by an optical way. The optical synapse is constructed on the base of an erbium-doped fiber laser, whose pumped diode current is driven by a pre-synaptic FitzHugh–Nagumo electronic neuron, and the laser output controls a post-synaptic FitzHugh–Nagumo electronic neuron. The implemented laser synapse displays very rich dynamics, including fixed points, periodic orbits with different frequency-locking ratios and chaos. These regimes can be beneficial for efficient biorobotics, where behavioral flexibility subserved by synaptic connectivity is a challenge.

  6. Mapping homeostatic synaptic plasticity using cable properties of dendrites.

    Science.gov (United States)

    Queenan, B N; Lee, K J; Tan, H; Huganir, R L; Vicini, S; Pak, D T S

    2016-02-19

    When chronically silenced, cortical and hippocampal neurons homeostatically upregulate excitatory synaptic function. However, the subcellular position of such changes on the dendritic tree is not clear. We exploited the cable-filtering properties of dendrites to derive a parameter, the dendritic filtering index (DFI), to map the spatial distribution of synaptic currents. Our analysis indicates that young rat cortical neurons globally scale AMPA receptor-mediated currents, while mature hippocampal neurons do not, revealing distinct homeostatic strategies between brain regions and developmental stages. The DFI presents a useful tool for mapping the dendritic origin of synaptic currents and the location of synaptic plasticity changes.

  7. Multi-gate synergic modulation in laterally coupled synaptic transistors

    Science.gov (United States)

    Zhu, Li Qiang; Xiao, Hui; Liu, Yang Hui; Wan, Chang Jin; Shi, Yi; Wan, Qing

    2015-10-01

    Laterally coupled oxide-based synaptic transistors with multiple gates are fabricated on phosphorosilicate glass electrolyte films. Electrical performance of the transistor can be evidently improved when the device is operated in a tri-gate synergic modulation mode. Excitatory post-synaptic current and paired pulse facilitation (PPF) behavior of biological synapses are mimicked, and PPF index can be effectively tuned by the voltage applied on the modulatory terminal. At last, superlinear to sublinear synaptic integration regulation is also mimicked by applying a modulatory pulse on the third modulatory terminal. The multi-gate oxide-based synaptic transistors may find potential applications in biochemical sensors and neuromorphic systems.

  8. Mild hypoxia affects synaptic connectivity in cultured neuronal networks.

    Science.gov (United States)

    Hofmeijer, Jeannette; Mulder, Alex T B; Farinha, Ana C; van Putten, Michel J A M; le Feber, Joost

    2014-04-01

    Eighty percent of patients with chronic mild cerebral ischemia/hypoxia resulting from chronic heart failure or pulmonary disease have cognitive impairment. Overt structural neuronal damage is lacking and the precise cause of neuronal damage is unclear. As almost half of the cerebral energy consumption is used for synaptic transmission, and synaptic failure is the first abrupt consequence of acute complete anoxia, synaptic dysfunction is a candidate mechanism for the cognitive deterioration in chronic mild ischemia/hypoxia. Because measurement of synaptic functioning in patients is problematic, we use cultured networks of cortical neurons from new born rats, grown over a multi-electrode array, as a model system. These were exposed to partial hypoxia (partial oxygen pressure of 150Torr lowered to 40-50Torr) during 3 (n=14) or 6 (n=8) hours. Synaptic functioning was assessed before, during, and after hypoxia by assessment of spontaneous network activity, functional connectivity, and synaptically driven network responses to electrical stimulation. Action potential heights and shapes and non-synaptic stimulus responses were used as measures of individual neuronal integrity. During hypoxia of 3 and 6h, there was a statistically significant decrease of spontaneous network activity, functional connectivity, and synaptically driven network responses, whereas direct responses and action potentials remained unchanged. These changes were largely reversible. Our results indicate that in cultured neuronal networks, partial hypoxia during 3 or 6h causes isolated disturbances of synaptic connectivity.

  9. Changes in synaptic and extrasynaptic N-methyl-D-aspartate receptor-mediated currents at early-stage epileptogenesis in adult mice

    Institute of Scientific and Technical Information of China (English)

    Juegang Ju; Sheng-tian Li

    2011-01-01

    Previous reports have shown that N-methyl-D-aspartate (NMDA) receptors are extensively involved in epilepsy genesis and recurrence.Recent studies have shown that synaptic and extrasynaptic NMDA receptors play different, or even opposing, roles in various signaling pathways, including synaptic plasticity and neuronal death.The present study analyzed changes in synaptic and extrasynaptic NMDA receptor-mediated currents during epilepsy onset.Mouse models of lithium chloride pilocarpine-induced epilepsy were established, and hippocampal slices were prepared at 24 hours after the onset of status epilepticus.Synaptic and extrasynaptic NMDA receptor-mediated excitatory post-synaptic currents (NMDA-EPSCs) were recorded in CA1 pyramidal neurons by whole-cell patch clamp technique.Results demonstrated no significant difference in rise and delay time of synaptic NMDA-EPSCs compared with normal neurons.Peak amplitude, area-to-peak ratio,and rising time of extrasynaptic NMDA-EPSCs remained unchanged, but decay of extrasynaptic NMDA-EPSCs was faster than that of normal neurons.These results suggest that extrasynaptic NMDA receptors play a role in epileptogenesis.

  10. Strain-dependent variations in spatial learning and in hippocampal synaptic plasticity in the dentate gyrus of freely behaving rats

    Directory of Open Access Journals (Sweden)

    Denise eManahan-Vaughan

    2011-03-01

    Full Text Available Hippocampal synaptic plasticity is believed to comprise the cellular basis for spatial learning. Strain-dependent differences in synaptic plasticity in the CA1 region have been reported. However, it is not known whether these differences extend to other synapses within the trisynaptic circuit, although there is evidence for morphological variations within that path. We investigated whether Wistar and Hooded Lister (HL rat strains express differences in synaptic plasticity in the dentate gyrus in vivo. We also explored whether they exhibit differences in the ability to engage in spatial learning in an 8-arm radial maze. Basal synaptic transmission was stable over a 24h period in both rat strains, and the input-output relationship of both strains was not significantly different. Paired-pulse analysis revealed significantly less paired-pulse facilitation in the Hooded Lister strain when pulses were given 40-100 msec apart. Low frequency stimulation at 1Hz evoked long-term depression (>24h in Wistar and short-term depression (<2h in HL rats; 200Hz stimulation induced long-term potentiation (>24h in Wistar, and a transient, significantly smaller potentiation (<1h in HL rats, suggesting that HL rats have higher thresholds for expression of persistent synaptic plasticity. Training for 10d in an 8-arm radial maze revealed that HL rats master the working memory task faster than Wistar rats, although both strains show an equivalent performance by the end of the trial period. HL rats also perform more efficiently in a double working and reference memory task. On the other hand, Wistar rats show better reference memory performance on the final (8-10 days of training. Wistar rats were less active and more anxious than HL rats.These data suggest that strain-dependent variations in hippocampal synaptic plasticity occur in different hippocampal synapses. A clear correlation with differences in spatial learning is not evident however.

  11. Water/Oil Biphasic Hydroformylation of Higher Olefins over a TPPTS-Rh/SiO2 Catalyst

    Institute of Scientific and Technical Information of China (English)

    Hejun Zhu; Yunjie Ding; Fu Yang; Li Yan; Jianmin Xiong; Hongmei Yin; Liwu Lin

    2004-01-01

    A novel TPPTS-Rh/SiO2 catalyst, prepared by directly modifying a heterogeneous highsurface-area Rh/SiO2 catalyst with water-soluble TPPTS ligands, could decrease the resistance of mass transfer in water/oil biphasic media for the hydroformylation of higher olefins. The catalytic performance for hydroformylation on this biphasic TPPTS-Rh/SiO2 catalyst system was higher than those of the traditional biphasic HRhCO(TPPTS)3 systems, owing to the chemical bonds between the highly dispersed Rh metal particles and the TPPTS ligands. The catalyst system is applicable for hydroformylation of higher olefins such as 1-dodecene.

  12. Autophosphorylation of [alpha]CaMKII is Differentially Involved in New Learning and Unlearning Mechanisms of Memory Extinction

    Science.gov (United States)

    Kimura, Ryoichi; Silva, Alcino J.; Ohno, Masuo

    2008-01-01

    Accumulating evidence indicates the key role of [alpha]-calcium/calmodulin-dependent protein kinase II ([alpha]CaMKII) in synaptic plasticity and learning, but it remains unclear how this kinase participates in the processing of memory extinction. Here, we investigated the mechanism by which [alpha]CaMKII may mediate extinction by using…

  13. Low energy 40Ca + 40Ca collisions

    International Nuclear Information System (INIS)

    This paper deals with the classical microscopic study of 40Ca + 40Ca collisions. Fusion cross-sections (σsub(CF)) for various incident energies, energy variations with time, shape deformation and the life time of resonance scattering (T) have been studied. Comparison of 40Ca + 40Ca results with those of 16O + 16O have also been made. (author)

  14. Tissue-type plasminogen activator induces synaptic vesicle endocytosis in cerebral cortical neurons.

    Science.gov (United States)

    Yepes, M; Wu, F; Torre, E; Cuellar-Giraldo, D; Jia, D; Cheng, L

    2016-04-01

    The release of the serine proteinase tissue-type plasminogen activator (tPA) from the presynaptic terminal of cerebral cortical neurons plays a central role in the development of synaptic plasticity, adaptation to metabolic stress and neuronal survival. Our earlier studies indicate that by inducing the recruitment of the cytoskeletal protein βII-spectrin and voltage-gated calcium channels to the active zone, tPA promotes Ca(2+)-dependent translocation of synaptic vesicles (SVs) to the synaptic release site where they release their load of neurotransmitters into the synaptic cleft. Here we used a combination of in vivo and in vitro experiments to investigate whether this effect leads to depletion of SVs in the presynaptic terminal. Our data indicate that tPA promotes SV endocytosis via a mechanism that does not require the conversion of plasminogen into plasmin. Instead, we show that tPA induces calcineurin-mediated dynamin I dephosphorylation, which is followed by dynamin I-induced recruitment of the actin-binding protein profilin II to the presynaptic membrane, and profilin II-induced F-actin formation. We report that this tPA-induced sequence of events leads to the association of newly formed SVs with F-actin clusters in the endocytic zone. In summary, the data presented here indicate that following the exocytotic release of neurotransmitters tPA activates the mechanism whereby SVs are retrieved from the presynaptic membrane and endocytosed to replenish the pool of vesicles available for a new cycle of exocytosis. Together, these results indicate that in murine cerebral cortical neurons tPA plays a central role coupling SVs exocytosis and endocytosis. PMID:26820595

  15. alpha-Latrotoxin affects mitochondrial potential and synaptic vesicle proton gradient of nerve terminals.

    Science.gov (United States)

    Tarasenko, A S; Storchak, L G; Himmelreich, N H

    2008-02-01

    Ca(2+)-independent [(3)H]GABA release induced by alpha-latrotoxin was found to consist of two sequential processes: a fast initial release realized via exocytosis and more delayed outflow through the plasma membrane GABA transporters [Linetska, M.V., Storchak, L.G., Tarasenko, A.S., Himmelreich, N.H., 2004. Involvement of membrane GABA transporters in alpha-latrotoxin-stimulated [(3)H]GABA release. Neurochem. Int. 44, 303-312]. To characterize the toxin-stimulated events attributable to the transporter-mediated [(3)H]GABA release from rat brain synaptosomes we studied the effect of alpha-latrotoxin on membrane potentials and generation of the synaptic vesicles proton gradient, using fluorescent dyes: potential-sensitive rhodamine 6G and pH-sensitive acridine orange. We revealed that alpha-latrotoxin induced a progressive dose-dependent depolarization of mitochondrial membrane potential and an irreversible run-down of the synaptic vesicle proton gradient. Both processes were insensitive to the presence of cadmium, a potent blocker of toxin-formed transmembrane pores, indicating that alpha-latrotoxin-induced disturbance of the plasma membrane permeability was not responsible to these effects. A gradual dissipation of the synaptic vesicle proton gradient closely coupled with lowering the vesicular GABA transporter activity results in a leakage of the neurotransmitter from synaptic vesicles to cytoplasm. As a consequence, there is an essential increase in GABA concentration in a soluble cytosolic pool that appears to be critical parameter for altering the mode of the plasma membrane GABA transporter operation from inward to outward. Thus, our data allow clarifying what cell processes underlain a recruitment of the plasma membrane transporter-mediated pathway in alpha-LTX-stimulated secretion.

  16. Impaired hippocampal synaptic plasticity and NR2A/2B expression ratio in remifentanil withdrawal rats.

    Science.gov (United States)

    Wang, Yi-Yi; Liu, Shichang; Zhang, Nan; Yang, Jing; Zhang, Yinguo

    2016-03-01

    Remifentanil is a kind of synthetic opioid which has gained wide clinical acceptance by anesthesiologists. In this study, we attempted to test whether withdrawal effects on learning mechanisms can be triggered by repeated low-dose remifentanil treatment. Male Sprague-Dawley (SD) rats were subjected to remifentanil (50μg/kgs.c.) twice per day at 12h intervals for 15 days. When the animals of remifentanil group were withdrawn from remifentanil at 10h after the last injection, changes in open field test, Morris water maze test (MWM) and synaptic efficacy were examined in each group. We demonstrated that repeated exposure to 50μg/kg remifentanil produced enhanced locomotor activity indicating that a remifentanil addiction animal model in rats was established. MWM results showed that exposure to remifentanil had no influence on the spatial cognition. After withdrawal of remifentanil rats showed impaired spatial cognition. In electrophysiology test, remifentanil group rats showed a trend for a rightward shift of input/output relationship and significant deficits in maintenance of STP and LTP. Immunohistochemistry results demonstrated increased NR2A/NR2B ratio that should be included depression of LTP. In the whole-cell patch-clamp recording, after elimination from remifentanil incubation, mEPSC frequency was down regulated in hippocampal CA1 neurons, indicating that basal synaptic transmission were affected by remifentanil withdrawal. Taken together, the current findings demonstrate that the remifentanil withdrawn rats exhibit obvious impairment of hippocampus-dependent memory and synaptic plasticity. Increased hippocampal NR2A/NR2B expression ratio and the changes of basal synaptic transmission may participate in the impairment of LTP. PMID:26777139

  17. Synaptic Democracy and Vesicular Transport in Axons

    Science.gov (United States)

    Bressloff, Paul C.; Levien, Ethan

    2015-04-01

    Synaptic democracy concerns the general problem of how regions of an axon or dendrite far from the cell body (soma) of a neuron can play an effective role in neuronal function. For example, stimulated synapses far from the soma are unlikely to influence the firing of a neuron unless some sort of active dendritic processing occurs. Analogously, the motor-driven transport of newly synthesized proteins from the soma to presynaptic targets along the axon tends to favor the delivery of resources to proximal synapses. Both of these phenomena reflect fundamental limitations of transport processes based on a localized source. In this Letter, we show that a more democratic distribution of proteins along an axon can be achieved by making the transport process less efficient. This involves two components: bidirectional or "stop-and-go" motor transport (which can be modeled in terms of advection-diffusion), and reversible interactions between motor-cargo complexes and synaptic targets. Both of these features have recently been observed experimentally. Our model suggests that, just as in human societies, there needs to be a balance between "efficiency" and "equality".

  18. Effect of developmental lead exposure on synaptic plasticity and N—methyl—D—aspartate receptor subunit in rat hippocampus

    Institute of Scientific and Technical Information of China (English)

    RuanDY; SuiL

    2002-01-01

    Chronic lead(Pb) exposure is known to be associated with learning and memory,and cognitive dysfunction in children.Previous studies have demonstrated that Pb exposure may impair neuronal process underlying synaptic plasticity via a direct interaction with N-methyl-D-aspartate (NMDA) receptors(NMDARs).The studies described here were carried out to investigate effect of developmental Pb exposure on long-term potentiation(LTP),long-tern depression(LTD) and NMDAs subunits in rat hippocampus.The results are listed as follows:(1)low-level Pb exposture can impair the induction and maintenance of LTP in vivo and in vitro;(2)the Pb-induced impairment of LTD magnitude was an age-related decline in area CA1 of rat hippocampus;(3)chronic Pb exposure affected two components,voltage-gated calcium channel-dependent LTD and NMDARs-dependent LTD,of LTD induction in area CA1 of rat hippocampus;(4)different effects of developmental Pb exposure on NMDA receptor NR1,NR2A,NR2B,NR2C,NR2D and NR3A subunits in area CA1,CA2,CA3 and CA4 of rat hippocampus were observed;(5)the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors enriched in area CA1,CA3 and dentate gyrus and kainite receptors enriched in area CA1 and dentate gyrus of rat hippocampus were impaired by Pb exposure.

  19. EFFECT OF ELECTROACUPUNCTURE ON SYNAPTIC PLASTICITY OF HPPOCAMPAL NEURONS IN CEREBRAL ISCHEMIA RATS

    Institute of Scientific and Technical Information of China (English)

    杨卓欣; 于海波; 王玲; 张家维

    2004-01-01

    Objective:To observe the effect of electroacupuncture (EA) on synaptic structure of hippocampal nerve felts and synaptophysin(SYN)expression in rats with cerebral ischemic injury. Methods: Sixty Wistar rats were randomized into sham-operation group, cerebral ischemia (CI) group and EA group, each of which was further divided into 1week (W) and 5W subgroups. CI injury model was established by occlusion of the bilateral common carotid arteries. "Baihui"(百会 GV 20), "Dazhui" (大椎 GV 14), "Renzhong"(人中 GV 26) and "Guanyuan"(关元 CV 4) were punctured and stimulated electrically. The brain tissue sections containing hippocampus region were stained with immunohistochemical technique and observed under light microscope and transmission electronic microscope. Results: After CI, the ischemic injury as degeneration of the presynapse compositions, decrease of the synaptic numeral density, and low expression of SYN were observed in hippocampal CA1 area. By the 5th week after CI, the neonatal synapses of CI and EA groups appeared, and SYN expression was upregulated. In EA group, the recovery of the numeral density of synapses was especially noticeable, being 93.8% of that of sham-operation group and significantly higher than that in CI group (P<0.01). Compared with sham-operation group, the calibrated optical density (COD) values of SYN increased to 70% in CI group, and 93.3% in EA group, and COD value in EA group was significantly higher than that in CI group (P<0.01). Conclusion: EA can function in promoting synaptic regeneration and enhancing and perfecting the actions of the reconstructed synapses in hippocampal CA1 area in CI rats.

  20. Orexin A induces bidirectional modulation of synaptic plasticity: Inhibiting long-term potentiation and preventing depotentiation.

    Science.gov (United States)

    Lu, Guan-Ling; Lee, Chia-Hsu; Chiou, Lih-Chu

    2016-08-01

    The orexin system consists of two peptides, orexin A and B and two receptors, OX1R and OX2R. It is implicated in learning and memory regulation while controversy remains on its role in modulating hippocampal synaptic plasticity in vivo and in vitro. Here, we investigated effects of orexin A on two forms of synaptic plasticity, long-term potentiation (LTP) and depotentiation of field excitatory postsynaptic potentials (fEPSPs), at the Schaffer Collateral-CA1 synapse of mouse hippocampal slices. Orexin A (≧30 nM) attenuated LTP induced by theta burst stimulation (TBS) in a manner antagonized by an OX1R (SB-334867), but not OX2R (EMPA), antagonist. Conversely, at 1 pM, co-application of orexin A prevented the induction of depotentiation induced by low frequency stimulation (LFS), i.e. restoring LTP. This re-potentiation effect of sub-nanomolar orexin A occurred at LFS of 1 Hz, but not 2 Hz, and with LTP induced by either TBS or tetanic stimulation. It was significantly antagonized by SB-334867, EMPA and TCS-1102, selective OX1R, OX2R and dual OXR antagonists, respectively, and prevented by D609, SQ22536 and H89, inhibitors of phospholipase C (PLC), adenylyl cyclase (AC) and protein kinase A (PKA), respectively. LFS-induced depotentiation was antagonized by blockers of NMDA, A1-adenosine and type 1/5 metabotropic glutamate (mGlu1/5) receptors, respectively. However, orexin A (1 pM) did not affect chemical-induced depotentiation by agonists of these receptors. These results suggest that orexin A bidirectionally modulates hippocampal CA1 synaptic plasticity, inhibiting LTP via OX1Rs at moderate concentrations while inducing re-potentiation via OX1Rs and OX2Rs, possibly through PLC and AC-PKA signaling at sub-nanomolar concentrations. PMID:26965217

  1. The role of growth retardation in lasting effects of neonatal dexamethasone treatment on hippocampal synaptic function.

    Directory of Open Access Journals (Sweden)

    Yu-Chen Wang

    Full Text Available BACKGROUND: Dexamethasone (DEX, a synthetic glucocorticoid, is commonly used to prevent or lessen the morbidity of chronic lung disease in preterm infants. However, evidence is now increasing that this clinical practice negatively affects somatic growth and may result in long-lasting neurodevelopmental deficits. We therefore hypothesized that supporting normal somatic growth may overcome the lasting adverse effects of neonatal DEX treatment on hippocampal function. METHODOLOGY/PRINCIPAL FINDINGS: To test this hypothesis, we developed a rat model using a schedule of tapering doses of DEX similar to that used in premature infants and examined whether the lasting influence of neonatal DEX treatment on hippocampal synaptic plasticity and memory performance are correlated with the deficits in somatic growth. We confirmed that neonatal DEX treatment switched the direction of synaptic plasticity in hippocampal CA1 region, favoring low-frequency stimulation- and group I metabotropic glutamate receptor agonist (S-3,5,-dihydroxyphenylglycine-induced long-term depression (LTD, and opposing the induction of long-term potentiation (LTP by high-frequency stimulation in the adolescent period. The effects of DEX on LTP and LTD were correlated with an increase in the autophosphorylation of Ca(2+/calmodulin-dependent protein kinase II at threonine-286 and a decrease in the protein phosphatase 1 expression. Neonatal DEX treatment resulted in a disruption of memory retention subjected to object recognition task and passive avoidance learning. The adverse effects of neonatal DEX treatment on hippocampal synaptic plasticity and memory performance of the animals from litters culled to 4 pups were significantly less than those for the 8-pup litters. However, there was no significant difference in maternal care between groups. CONCLUSION/SIGNIFICANCE: Our results demonstrate that growth retardation plays a crucial role in DEX-induced long-lasting influence of

  2. Ubiquitination-dependent mechanisms regulate synaptic growth and function.

    Science.gov (United States)

    DiAntonio, A; Haghighi, A P; Portman, S L; Lee, J D; Amaranto, A M; Goodman, C S

    2001-07-26

    The covalent attachment of ubiquitin to cellular proteins is a powerful mechanism for controlling protein activity and localization. Ubiquitination is a reversible modification promoted by ubiquitin ligases and antagonized by deubiquitinating proteases. Ubiquitin-dependent mechanisms regulate many important processes including cell-cycle progression, apoptosis and transcriptional regulation. Here we show that ubiquitin-dependent mechanisms regulate synaptic development at the Drosophila neuromuscular junction (NMJ). Neuronal overexpression of the deubiquitinating protease fat facets leads to a profound disruption of synaptic growth control; there is a large increase in the number of synaptic boutons, an elaboration of the synaptic branching pattern, and a disruption of synaptic function. Antagonizing the ubiquitination pathway in neurons by expression of the yeast deubiquitinating protease UBP2 (ref. 5) also produces synaptic overgrowth and dysfunction. Genetic interactions between fat facets and highwire, a negative regulator of synaptic growth that has structural homology to a family of ubiquitin ligases, suggest that synaptic development may be controlled by the balance between positive and negative regulators of ubiquitination.

  3. The Ubiquitin-Proteasome Pathway and Synaptic Plasticity

    Science.gov (United States)

    Hegde, Ashok N.

    2010-01-01

    Proteolysis by the ubiquitin-proteasome pathway (UPP) has emerged as a new molecular mechanism that controls wide-ranging functions in the nervous system, including fine-tuning of synaptic connections during development and synaptic plasticity in the adult organism. In the UPP, attachment of a small protein, ubiquitin, tags the substrates for…

  4. Synaptic Tagging, Evaluation of Memories, and the Distal Reward Problem

    Science.gov (United States)

    Papper, Marc; Kempter, Richard; Leibold, Christian

    2011-01-01

    Long-term synaptic plasticity exhibits distinct phases. The synaptic tagging hypothesis suggests an early phase in which synapses are prepared, or "tagged," for protein capture, and a late phase in which those proteins are integrated into the synapses to achieve memory consolidation. The synapse specificity of the tags is consistent with…

  5. Synaptic signaling and aberrant RNA splicing in autism spectrum disorders

    OpenAIRE

    Ryan M Smith; Wolfgang eSadee

    2011-01-01

    Interactions between presynaptic and postsynaptic cellular adhesion molecules drive synapse maturation during development. These trans-synaptic interactions are regulated by alternative splicing of cellular adhesion molecule RNAs, which ultimately determines neurotransmitter phenotype. The diverse assortment of RNAs produced by alternative splicing generates countless protein isoforms necessary for guiding specialized cell-to-cell connectivity. Failure to generate the appropriate synaptic ...

  6. Dynamic changes in cytosolic ATP levels in cultured glutamatergic neurons during NMDA-induced synaptic activity supported by glucose or lactate

    DEFF Research Database (Denmark)

    Lange, Sofie Cecilie; Winkler, Ulrike; Andresen, Lars;

    2015-01-01

    following NMDA-induced neurotransmission activity, as indicated by a reversible 10-20 % decrease in the response of the biosensor. The responses were absent when the NMDA receptor antagonist memantine was present. In the presence of lactate alone, the ATP response dropped significantly more than...... biosensor Ateam1.03YEMK. While inducing synaptic activity by subjecting cultured neurons to two 30 s pulses of NMDA (30 µM) with a 4 min interval, changes in relative ATP levels were measured in the presence of lactate (1 mM), glucose (2.5 mM) or the combination of the two. ATP levels reversibly declined...... in the presence of glucose following the 2nd pulse of NMDA (approx. 10 vs. 20 %). Further, cytosolic Ca(2+) homeostasis during NMDA-induced synaptic transmission is partially inhibited by verapamil indicating that voltage-gated Ca(2+) channels are activated. Lastly, we showed that cytosolic Ca(2+) homeostasis...

  7. Cdk5 Modulates Long-Term Synaptic Plasticity and Motor Learning in Dorsolateral Striatum.

    Science.gov (United States)

    Hernandez, Adan; Tan, Chunfeng; Mettlach, Gabriel; Pozo, Karine; Plattner, Florian; Bibb, James A

    2016-01-01

    The striatum controls multiple cognitive aspects including motivation, reward perception, decision-making and motor planning. In particular, the dorsolateral striatum contributes to motor learning. Here we define an approach for investigating synaptic plasticity in mouse dorsolateral cortico-striatal circuitry and interrogate the relative contributions of neurotransmitter receptors and intracellular signaling components. Consistent with previous studies, we show that long-term potentiation (LTP) in cortico-striatal circuitry is facilitated by dopamine, and requires activation of D1-dopamine receptors, as well as NMDA receptors (NMDAR) and their calcium-dependent downstream effectors, including CaMKII. Moreover, we assessed the contribution of the protein kinase Cdk5, a key neuronal signaling molecule, in cortico-striatal LTP. Pharmacological Cdk5 inhibition, brain-wide Cdk5 conditional knockout, or viral-mediated dorsolateral striatal-specific loss of Cdk5 all impaired dopamine-facilitated LTP or D1-dopamine receptor-facilitated LTP. Selective loss of Cdk5 in dorsolateral striatum increased locomotor activity and attenuated motor learning. Taken together, we report an approach for studying synaptic plasticity in mouse dorsolateral striatum and critically implicate D1-dopamine receptor, NMDAR, Cdk5, and CaMKII in cortico-striatal plasticity. Furthermore, we associate striatal plasticity deficits with effects upon behaviors mediated by this circuitry. This approach should prove useful for the study of the molecular basis of plasticity in the dorsolateral striatum. PMID:27443506

  8. Enhanced dibenzothiophene biodesulfurization by immobilized cells of Brevibacterium lutescens in n-octane-water biphasic system.

    Science.gov (United States)

    Dai, Yong; Shao, Rong; Qi, Gang; Ding, Bin-Bin

    2014-11-01

    In this study, it was the first report that the Brevibacterium lutescens CCZU12-1 was employed as a sulfur removing bacteria. Using dibenzothiophene (DBT) as the sole sulfur source, B. lutescens could selectively degrade DBT into 2-hydroxybiphenyl (2-HBP) via the "4S" pathway. In the basal salt medium (BSM) supplemented with 0.25 mM DBT and 0.5 g/L Tween-80, high desulfurization rate (100 %) was obtained by growth cells after 60 h. Furthermore, the n-octane-water (10:90, v/v) biphasic system was built for the biodesulfurization by resting cells. Moreover, a combination of magnetic nano Fe3O4 particles with calcium alginate immobilization was used for enhancing biodesulfurization. In this n-octane-water biphasic system, immobilized B. lutescens cells could be reused for not less than four times. Therefore, B. lutescens CCZU12-1 shows high potential in the biodesulfurization. PMID:25173674

  9. Microstructure Evolution of Biphasic TiNi1+ x Sn Thermoelectric Materials

    Science.gov (United States)

    Verma, Nisha; Douglas, Jason E.; Krämer, Stephan; Pollock, Tresa M.; Seshadri, Ram; Levi, Carlos G.

    2016-08-01

    The effects of thermal treatment on the microstructure of biphasic materials comprising half-Heusler (hH) and full-Heusler (fH) phases, as well as on their associated thermal conductivity, are discussed. The focus of this study was on a biphasic hH/fH alloy of nominal stoichiometry TiNi1.2Sn, synthesized by containerless (magnetic levitation) induction melting. The alloy samples were exposed to various heat treatments to generate microstructures containing second-phase precipitates ranging in size from ~10 nm to a few micrometers. The materials were characterized with regard to morphology, size, shape, and orientation relationship of the fH and hH phases, both of which were present as precipitates within larger regions of the counterpart phase. The solidification path of the alloy and its implications for the subsequent microstructure evolution during heat treatment were elucidated, and relationships with the ensuing thermal conductivity were characterized.

  10. A method for separating water soluble organics from a process stream by aqueous biphasic extraction

    Energy Technology Data Exchange (ETDEWEB)

    Chaiko, David J.; Mego, William A.

    1997-12-01

    The present invention relates to a method for separating water-miscible organic species from a process stream by aqueous biphasic extraction. In particular, the method includes extracting the organic species into a polymer-rich phase of an aqueous biphase system in which the process stream comprises the salt-rich phase, and, next, separating the polymer from the extracted organic species by contacting the loaded, polymer-rich phase with a water-immiscible organic phase. Alternatively, the polymer can be separated from the extracted organic species by raising the temperature of the loaded, polymer-rich phase above the cloud point, such that the polymer and the water-soluble organic species separate into two distinct aqueous phases. In either case, a substantially salt-free, concentrated aqueous solution containing the organic species is recovered.

  11. Biphasic and boundary lubrication mechanisms in artificial hydrogel cartilage: A review.

    Science.gov (United States)

    Murakami, Teruo; Yarimitsu, Seido; Nakashima, Kazuhiro; Sakai, Nobuo; Yamaguchi, Tetsuo; Sawae, Yoshinori; Suzuki, Atsushi

    2015-12-01

    Various studies on the application of artificial hydrogel cartilage to cartilage substitutes and artificial joints have been conducted. It is expected in clinical application of artificial hydrogel cartilage that not only soft-elastohydrodynamic lubrication but biphasic, hydration, gel-film and boundary lubrication mechanisms will be effective to sustain extremely low friction and minimal wear in daily activities similar to healthy natural synovial joints with adaptive multimode lubrication. In this review article, the effectiveness of biphasic lubrication and boundary lubrication in hydrogels in thin film condition is focused in relation to the structures and properties of hydrogels. As examples, the tribological behaviors in three kinds of poly(vinyl alcohol) hydrogels with high water content are compared, and the importance of lubrication mechanism in biomimetic artificial hydrogel cartilage is discussed to extend the durability of cartilage substitute.

  12. Efficacy and safety of biphasic insulin aspart and biphasic insulin lispro mix in patients with type 2 diabetes: A review of the literature.

    Science.gov (United States)

    Kumar, Ajay

    2016-01-01

    Type 2 diabetes (T2D) represents an escalating burden worldwide, particularly in China and India. Compared with Caucasians, Asian people with diabetes have lower body mass index, increased visceral adiposity, and postprandial glucose (PPG)/insulin resistance. Since postprandial hyperglycemia contributes significantly to total glycemic burden and is associated with heightened cardiovascular risk, targeting PPG early in T2D is paramount. Premixed insulin regimens are widely used in Asia due to their convenience and effectiveness. Data from randomized controlled trials and observational studies comparing efficacy and safety of biphasic insulin aspart 30 (BIAsp 30) with biphasic insulin lispro mix (LM 25/50) and versus other insulin therapies or oral antidiabetic drugs (OADs) in T2D demonstrated that BIAsp 30 and LM 25/50 were associated with similar or greater improvements in glycemic control versus comparator regimens, such as basal-bolus insulin, in insulin-naÏve, and prior insulin users. Studies directly comparing BIAsp 30 and LM 25 provided conflicting glycemic control results. Safety data generally showed increased hypoglycemia and weight gain with premixed insulins versus basal-bolus insulin or OADs. However, large observational trials documented improvements in glycated hemoglobin, PPG, and hypoglycemia with BIAsp 30 in multi-ethnic patient populations. In summary, this literature review demonstrates that premixed insulin regimens are an appropriate and effective treatment choice in T2D. PMID:27186543

  13. Biphasic Insulin Aspart 30/70: Pharmacokinetics and Pharmacodynamics Compared With Once-Daily Biphasic Human Insulin and Basal-Bolus Therapy

    Science.gov (United States)

    Heise, Tim; Heinemann, Lutz; Hövelmann, Ulrike; Brauns, Bianca; Nosek, Leszek; Haahr, Hanne L.; Olsen, Klaus J.

    2009-01-01

    OBJECTIVE Pharmacological profiles of biphasic insulin aspart 30/70 (BIAsp 30) once daily (OD), twice daily (b.i.d.), and three times daily (t.i.d.) were compared with other insulin regimens in two crossover glucose clamp studies of insulin-treated type 2 diabetic patients. RESEARCH DESIGNS AND METHODS Study 1 consisted of BIAsp 30 OD, b.i.d., and t.i.d. versus biphasic human insulin 30/70 (BHI 30), OD (n = 24). Study 2 examined BIAsp 30 t.i.d. versus basal-bolus therapy (insulin glargine OD plus insulin glulisine t.i.d.) (n = 24). Pharmacokinetics/pharmacodynamics (PK/PD) were investigated over 24 h. RESULTS Study 1: PK and PD were markedly different between BIAsp 30 OD and BHI 30 OD: the maximum insulin concentration and glucose infusion rate (GIR) were higher for BIAsp 30; time to maximum metabolism was 1.7 h sooner for BIAsp 30. Study 2: both regimens showed three distinct prandial-related GIR peaks. GIR 24-h area under the curve for BIAsp t.i.d. was higher than for basal-bolus therapy: 2,585.2 vs. 2,289.2 mg/kg. CONCLUSIONS BIAsp had pharmacological advantages over BHI. BIAsp t.i.d. had a similar PD profile to basal-bolus therapy. PMID:19487640

  14. Efficacy and safety of biphasic insulin aspart and biphasic insulin lispro mix in patients with type 2 diabetes: A review of the literature

    Directory of Open Access Journals (Sweden)

    Ajay Kumar

    2016-01-01

    Full Text Available Type 2 diabetes (T2D represents an escalating burden worldwide, particularly in China and India. Compared with Caucasians, Asian people with diabetes have lower body mass index, increased visceral adiposity, and postprandial glucose (PPG/insulin resistance. Since postprandial hyperglycemia contributes significantly to total glycemic burden and is associated with heightened cardiovascular risk, targeting PPG early in T2D is paramount. Premixed insulin regimens are widely used in Asia due to their convenience and effectiveness. Data from randomized controlled trials and observational studies comparing efficacy and safety of biphasic insulin aspart 30 (BIAsp 30 with biphasic insulin lispro mix (LM 25/50 and versus other insulin therapies or oral antidiabetic drugs (OADs in T2D demonstrated that BIAsp 30 and LM 25/50 were associated with similar or greater improvements in glycemic control versus comparator regimens, such as basal–bolus insulin, in insulin-naÏve, and prior insulin users. Studies directly comparing BIAsp 30 and LM 25 provided conflicting glycemic control results. Safety data generally showed increased hypoglycemia and weight gain with premixed insulins versus basal–bolus insulin or OADs. However, large observational trials documented improvements in glycated hemoglobin, PPG, and hypoglycemia with BIAsp 30 in multi-ethnic patient populations. In summary, this literature review demonstrates that premixed insulin regimens are an appropriate and effective treatment choice in T2D.

  15. Nicotinic mechanisms influencing synaptic plasticity in the hippocampus

    Institute of Scientific and Technical Information of China (English)

    Andon Nicholas PLACZEK; Tao A ZHANG; John Anthony DANI

    2009-01-01

    Nicotinic acetylcholine receptors (nAChRs) are expressed throughout the hippocampus, and nicotinic signaling plays an important role in neuronal function. In the context of learning and memory related behaviors associated with hippocampal function, a potentially significant feature of nAChR activity is the impact it has on synaptic plasticity. Synaptic plasticity in hippocampal neurons has long been considered a contributing cellular mechanism of learning and memory. These same kinds of cellular mechanisms are a factor in the development of nicotine addiction. Nicotinic signaling has been demonstrated by in vitro studies to affect synaptic plasticity in hippocampal neurons via multiple steps, and the signaling has also been shown to evoke synaptic plasticity in vivo. This review focuses on the nAChRs subtypes that contribute to hippocampal synaptic plasticity at the cellular and circuit level. It also considers nicotinic influences over long-term changes in the hippocampus that may contribute to addiction.

  16. Size and receptor density of glutamatergic synapses: a viewpoint from left-right asymmetry of CA3-CA1 connections

    Directory of Open Access Journals (Sweden)

    Yoshiaki Shinohara

    2009-07-01

    Full Text Available Synaptic plasticity is considered to be the main mechanism for learning and memory. Excitatory synapses in the cerebral cortex and hippocampus undergo plastic changes during development and in response to electric stimulation. It is widely accepted that this process is mediated by insertion and elimination of various glutamate receptors. In a series of recent investigations on left-right asymmetry of hippocampal CA3-CA1 synapses, glutamate receptor subunits have been found to have distinctive expression patterns that depend on the postsynaptic density (PSD area. Particularly notable are the GluR1 AMPA receptor subunit and NR2B NMDA receptor subunit, where receptor density has either a supra-linear (GluR1 AMPA or inverse (NR2B NMDAR relationship to the PSD area. We review current understanding of structural and physiological synaptic plasticity and propose a scheme to classify receptor subtypes by their expression pattern with respect to PSD area.

  17. Biphasic gastroretentive drug delivery system of acyclovir: formulation and in vitro evaluation

    OpenAIRE

    Bandari, Suresh; Yamsani, Madhusudan R.

    2010-01-01

    A biphasic gastroretentive drug delivery system of acyclovir consisted of loading dose tablet and floating multiple matrix tablets was prepared by direct compression process. The delivery system was designed by hydroxy propyl methyl cellulose as retardant polymer with an effervescent component to get the desired buoyant and sustained release characteristics. All formulations compile within the limits. The FTIR studies did not show any evidence of an interaction between acyclovir a...

  18. A biphasic oxidation of alcohols to aldehydes and ketones using a simplified packed-bed microreactor

    OpenAIRE

    Andrew Bogdan; D. Tyler McQuade

    2009-01-01

    We demonstrate the preparation and characterization of a simplified packed-bed microreactor using an immobilized TEMPO catalyst shown to oxidize primary and secondary alcohols via the biphasic Anelli-Montanari protocol. Oxidations occurred in high yields with great stability over time. We observed that plugs of aqueous oxidant and organic alcohol entered the reactor as plugs but merged into an emulsion on the packed-bed. The emulsion coalesced into larger plugs upon exiting the reactor, leavi...

  19. Ultra-rapid growth of biphasic nanowires in micro- and hypergravity.

    Science.gov (United States)

    Veith, Michael; Lee, Juseok; Schmid, Herbert; Aktas, Cenk

    2013-04-01

    Aluminium/aluminium oxide wires form under microgravity, earth conditions, and hypergravity in different forms. While under 0.04 G the biphasic wires are predominantly linear, they form bundles of wires of high curvature at 1 G and 1.8 G. The absence (0.04 G) and presence (1 G, 1.8 G) of gradients are reflected by the agglomeration and growth direction of the nanowires. PMID:23239577

  20. A biphase shift keying (BPSK), direct sequence, spread spectrum modem for Petite Amateur Navy Satellite (PANSAT).

    OpenAIRE

    Fritz, Thomas M.

    1992-01-01

    Approved for public release; distribution is unlimited The development of a bi-phase shift keying (BPSK), direct sequence, spread spectrum modem is conducted for the purpose of creating a prototype design to be implemented in the Petite Amateur Navy Satellite (PANSAT). The design discussion includes the hardware used in the functional realization of a working design. The design itself encompasses selection of components and demonstrates (through circuit diagrams and waveform...

  1. Changes in biphasic electrode impedance with protein adsorption and cell growth

    OpenAIRE

    Newbold, Carrie; Richardson, Rachael; Millard, Rodney; Huang, Christie; Milojevic, Dusan; Shepherd, Robert; Cowan, Robert

    2010-01-01

    This study was undertaken to assess the contribution of protein adsorption and cell growth to increases in electrode impedance that occur immediately following implantation of cochlear implant electrodes and other neural stimulation devices. An in vitro model of the electrode-tissue interface was used. Radiolabelled albumin in phosphate buffered saline was added to planar gold electrodes and electrode impedance measured using a charge-balanced biphasic current pulse. The polarisation impedanc...

  2. A Phenomenological Model of the Electrically Stimulated Auditory Nerve Fiber: Temporal and Biphasic Response Properties.

    Science.gov (United States)

    Horne, Colin D F; Sumner, Christian J; Seeber, Bernhard U

    2016-01-01

    We present a phenomenological model of electrically stimulated auditory nerve fibers (ANFs). The model reproduces the probabilistic and temporal properties of the ANF response to both monophasic and biphasic stimuli, in isolation. The main contribution of the model lies in its ability to reproduce statistics of the ANF response (mean latency, jitter, and firing probability) under both monophasic and cathodic-anodic biphasic stimulation, without changing the model's parameters. The response statistics of the model depend on stimulus level and duration of the stimulating pulse, reproducing trends observed in the ANF. In the case of biphasic stimulation, the model reproduces the effects of pseudomonophasic pulse shapes and also the dependence on the interphase gap (IPG) of the stimulus pulse, an effect that is quantitatively reproduced. The model is fitted to ANF data using a procedure that uniquely determines each model parameter. It is thus possible to rapidly parameterize a large population of neurons to reproduce a given set of response statistic distributions. Our work extends the stochastic leaky integrate and fire (SLIF) neuron, a well-studied phenomenological model of the electrically stimulated neuron. We extend the SLIF neuron so as to produce a realistic latency distribution by delaying the moment of spiking. During this delay, spiking may be abolished by anodic current. By this means, the probability of the model neuron responding to a stimulus is reduced when a trailing phase of opposite polarity is introduced. By introducing a minimum wait period that must elapse before a spike may be emitted, the model is able to reproduce the differences in the threshold level observed in the ANF for monophasic and biphasic stimuli. Thus, the ANF response to a large variety of pulse shapes are reproduced correctly by this model.

  3. Localized biphasic type malignant mesothelioma arising in the peritoneum: Report of a case

    OpenAIRE

    Kohno, Mikihiro; Maruyama, Riichiroh; Kitagawa, Dai; Sugimachi, Keishi; Kinjo, Mitsuru; Higashi, Hidefumi

    2014-01-01

    This report describes a rare case of localized malignant biphasic (mixed epithelioid and sarcomatoid) mesothelioma arising in the peritoneum. A 69-year-old male with a history of asbestos exposure, complaining of a painful mass in the left chest wall, was found via computed tomography (CT) to have a tumor in the left peritoneum. The resected tumor was histologically and immunohistochemically consistent with a malignant mesothelioma with mixed epithelioid and sarcomatoid type and no distant me...

  4. Dehydration of xylose to furfural over niobium phosphate catalyst in biphasic solvent system

    Institute of Scientific and Technical Information of China (English)

    Boonrat; Pholjaroen; Ning; Li; Zhiqiang; Wang; Aiqin; Wang; Tao; Zhang

    2013-01-01

    Phosphoric acid treated niobic acid(NbP)was used for the dehydration of xylose to furfural in biphasic solvent system,which was found to exhibit the best performance among the tested catalysts.The excellent performance of NbP could be explained by the better synergistic cooperation between Bro¨nsted and Lewis acid sites.Moreover,NbP showed good stability and no obvious deactivation or leaching of Nb could be observed after six continuous recycles.

  5. A simulation study of the reaction of human heart to biphasic electrical shocks

    Directory of Open Access Journals (Sweden)

    Seemann Gunnar

    2004-06-01

    Full Text Available Abstract Background This article presents a study, which examines the effects of biphasic electrical shocks on human ventricular tissue. The effects of this type of shock are not yet fully understood. Animal experiments showed the superiority of biphasic shocks over monophasic ones in defibrillation. A mathematical computer simulation can increase the knowledge of human heart behavior. Methods The research presented in this article was done with different models representing a three-dimensional wedge of ventricular myocardium. The electrophysiology was described with Priebe-Beuckelmann model. The realistic fiber twist, which is specific to human myocardium was included. Planar electrodes were placed at the ends of the longest side of the virtual cardiac wedge, in a bath medium. They were sources of electrical shocks, which varied in magnitude from 0.1 to 5 V. In a second arrangement ring electrodes were placed directly on myocardium for getting a better view on secondary electrical sources. The electrical reaction of the tissue was generated with a bidomain model. Results The reaction of the tissue to the electrical shock was specific to the initial imposed characteristics. Depolarization appeared in the first 5 ms in different locations. A further study of the cardiac tissue behavior revealed, which features influence the response of the considered muscle. It was shown that the time needed by the tissue to be totally depolarized is much shorter when a biphasic shock is applied. Each simulation ended only after complete repolarization was achieved. This created the possibility of gathering information from all states corresponding to one cycle of the cardiac rhythm. Conclusions The differences between the reaction of the homogeneous tissue and a tissue, which contains cleavage planes, reveals important aspects of superiority of biphasic pulses. ...

  6. A biphasic finite element study on the role of the articular cartilage superficial zone in confined compression

    OpenAIRE

    Guo, Hongqiang; Maher, Suzanne A; Torzilli, Peter A.

    2014-01-01

    The aim of this study was to investigate the role of the superficial zone on the mechanical behavior of articular cartilage. Confined compression of articular cartilage was modeled using a biphasic finite element analysis to calculate the one-dimensional deformation of the extracellular matrix (ECM) and movement of the interstitial fluid through the ECM and articular surface. The articular cartilage was modeled as an inhomogeneous, nonlinear hyperelastic biphasic material with depth and strai...

  7. The effect of two lipophilic gamma-aminobutyric acid uptake blockers in CA1 of the rat hippocampal slice

    DEFF Research Database (Denmark)

    Rekling, J C; Jahnsen, H; Mosfeldt Laursen, A

    1990-01-01

    the blood. 2. We have investigated the effect of these two uptake inhibitors on the responses to exogenous GABA and on GABA-mediated inhibitory synaptic potentials in pyramidal neurones of the CA1 region in the rat hippocampal slice. 3. We found that both drugs increased the amplitude and duration of...... responses to exogenous GABA. Furthermore, the inhibitory synaptic potentials increased in amplitude. This increase was seen in both early and late phases of the synaptic potentials. We conclude that NO-05-0328 and NO-05-0329, at least in vitro, are more effective than older GABA uptake inhibitors such as...

  8. STIM1 and Orai1 mediate thrombin-induced Ca(2+) influx in rat cortical astrocytes.

    Science.gov (United States)

    Moreno, Claudia; Sampieri, Alicia; Vivas, Oscar; Peña-Segura, Claudia; Vaca, Luis

    2012-12-01

    In astrocytes, thrombin leads to cytoplasmic Ca(2+) elevations modulating a variety of cytoprotective and cytotoxic responses. Astrocytes respond to thrombin stimulation with a biphasic Ca(2+) increase generated by an interplay between ER-Ca(2+) release and store-operated Ca(2+) entry (SOCE). In many cell types, STIM1 and Orai1 have been demonstrated to be central components of SOCE. STIM1 senses the ER-Ca(2+) depletion and binds Orai1 to activate Ca(2+) influx. Here we used immunocytochemistry, overexpression and siRNA assays to investigate the role of STIM1 and Orai1 in the thrombin-induced Ca(2+) response in primary cultures of rat cortical astrocytes. We found that STIM1 and Orai1 are endogenously expressed in cortical astrocytes and distribute accordingly with other mammalian cells. Importantly, native and overexpressed STIM1 reorganized in puncta under thrombin stimulation and this reorganization was reversible. In addition, the overexpression of STIM1 and Orai1 increased by twofold the Ca(2+) influx evoked by thrombin, while knockdown of endogenous STIM1 and Orai1 significantly decreased this Ca(2+) influx. These results indicate that STIM1 and Orai1 underlie an important fraction of the Ca(2+) response that astrocytes exhibit in the presence of thrombin. Thrombin stimulation in astrocytes leads to ER-Ca(2+) release which causes STIM1 reorganization allowing the activation of Orai1 and the subsequent Ca(2+) influx.

  9. Triclocarban-induced change in intracellular Ca²⁺ level in rat thymocytes: cytometric analysis with Fluo-3 under Zn²⁺-free conditions.

    Science.gov (United States)

    Miura, Yukari; Chen, Xiaohui; Yamada, Saki; Sugihara, Aya; Enkhjargal, Molomjamts; Sun, Yuanzhi; Kuroda, Keiko; Satoh, Masaya; Oyama, Yasuo

    2014-03-01

    Triclocarban (TCC) is an antimicrobial used in personal hygiene products. Recent health concerns arose after TCC was detected in the blood of human subjects who showered with soap containing TCC. In this study, the effect of TCC on intracellular Ca(2+) concentration in rat thymocytes was examined using Fluo-3, an indicator of intracellular Ca(2+). TCC at concentrations ranging from 0.1 μM to 3 μM increased intracellular Ca(2+) concentration biphasically: first by releasing Ca(2+) from intracellular Ca(2+) stores and then inducing Ca(2+) influx through store-operated Ca(2+) channels. The threshold TCC concentration to increase intracellular Ca(2+) concentration in this study was lower than the maximum TCC concentrations reported in human blood samples. Therefore, we anticipate that TCC at concentrations reported in human blood samples might disturb intracellular Ca(2+) signaling in human lymphocytes. PMID:24562054

  10. Synchronized oscillations of dimers in biphasic charged fd-virus suspensions

    Science.gov (United States)

    Kang, K.; Piao, S. H.; Choi, H. J.

    2016-08-01

    Micron-sized colloidal spheres that are dispersed in an isotropic-nematic biphasic host suspension of charged rods (fd-virus particles) are shown to spontaneously form dimers, which exhibit a synchronized oscillatory motion. Dimer formation is not observed in the monophase of isotropic and nematic suspensions. The synchronized oscillations of dimers are connected to the inhomogeneous state of the host suspension of charged rods (fd viruses) where nematic domains are in coexistence with isotropic regions. The synchronization of oscillations occurs in bulk states, in the absence of an external field. With a low field strength of an applied electric field, the synchronization is rather reduced, but it recovers again when the field is turned off. In this Rapid Communication, we report this observation as an example of the strange attractor, occurring in the mixture of PS (polystyrene) dimers in an isotropic-nematic coexistence biphasic fd-virus network. Furthermore, we highlight that the synchronization of PS-dimer oscillations is the result of a global bifurcation diagram, driven by a delicate balance between the short-attractive "twisted" interaction of PS dimers and long-ranged electrostatic repulsive interactions of charged fd rods. The interest is then in the local enhancement of "twist-nematic" elasticity in reorientation of the dimer oscillations. An analysis of image-time correlations is provided with the data movies and Fourier transforms of averaged orientations for the synchronized oscillations of dimers in the biphasic I -N coexistence concentration of charged fd-virus suspensions.

  11. Alzheimer's disease: synaptic dysfunction and Abeta

    LENUS (Irish Health Repository)

    Shankar, Ganesh M

    2009-11-23

    Abstract Synapse loss is an early and invariant feature of Alzheimer\\'s disease (AD) and there is a strong correlation between the extent of synapse loss and the severity of dementia. Accordingly, it has been proposed that synapse loss underlies the memory impairment evident in the early phase of AD and that since plasticity is important for neuronal viability, persistent disruption of plasticity may account for the frank cell loss typical of later phases of the disease. Extensive multi-disciplinary research has implicated the amyloid β-protein (Aβ) in the aetiology of AD and here we review the evidence that non-fibrillar soluble forms of Aβ are mediators of synaptic compromise. We also discuss the possible mechanisms of Aβ synaptotoxicity and potential targets for therapeutic intervention.

  12. Synaptic Transmission An Information-Theoretic Perspective

    CERN Document Server

    Manwani, A

    1998-01-01

    Here we analyze synaptic transmission from an information-theoretic perspective. We derive closed-form expressions for the lower-bounds on the capacity of a simple model of a cortical synapse under two explicit coding paradigms. Under the ``signal estimation'' paradigm, we assume the signal to be encoded in the mean firing rate of a Poisson neuron. The performance of an optimal linear estimator of the signal then provides a lower bound on the capacity for signal estimation. Under the ``signal detection'' paradigm, the presence or absence of the signal has to be detected. Performance of the optimal spike detector allows us to compute a lower bound on the capacity for signal detection. We find that single synapses (for empirically measured parameter values) transmit information poorly but significant improvement can be achieved with a small amount of redundancy.

  13. Elimination of redundant synaptic inputs in the absence of synaptic strengthening

    OpenAIRE

    Wang, Hao; Liu, Hong; Zhang, Zhong-wei

    2011-01-01

    Synaptic refinement, a developmental process that consists of selective elimination and strengthening of immature synapses, is essential for the formation of precise neuronal circuits and proper brain function. At glutamatergic synapses in the brain, activity-dependent recruitment of AMPA receptors (AMPAR) is a key mechanism underlying the strengthening of immature synapses. Studies using receptor over-expression have shown that the recruitment of AMPARs is subunit specific. With the notable ...

  14. Fabrication and materials properties of high-density polyethylene (HDPE)/biphasic calcium phosphate (BCP) hybrid bone plates

    International Nuclear Information System (INIS)

    Biphasic calcium phosphate-reinforced high-density polyethylene (BCP/HDPE) hybrid composite is a new orthopedic biomaterial, which was made to simulate a natural bone composition. Calcium phosphate systems and HDPE hybrid composites have been used in biomedical applications without any inflammatory response. Differences in natural bone of both materials have motivated the use of coupling agents to improve their interfacial interfacial interactions. The composites were prepared using medical grade BCP powder and granular polyethylene. This material was produced by replacing the mineral component and collagen soft tissue of the bone with BCP and HDPE, respectively. As expected, increased volume fraction of either reinforcement type over 0 ∼ 50 vol.% resulted in a increased Vickers hardness and Young's modulus. Thus, BCP particle-reinforced HDPE composites possessed improved material and mechanical properties. BCP particles-reinforced composites were anisotropic due to an alignment of the particles in the matrix during a processing. On the other hand, bending and tensile strength was dramatically changed in the matrix. To change the material and mechanical properties of HDPE/BCP composites, the process of a blending was used, and its effect on the microstructure and mechanical proprieties of HDPE/BCP composites were investigated by means of FT-IR/ATR spectroscopy, XRD, FE-SEM, Vickers Hardness Testing Machine, Universal Testing Machine, Mercury Porosimeter and Ultrasonic Flaw Detector at room temperature. For the evaluation of the cell viability and proliferation onto the external surface of HDPE/BCP hybrid plates with a HaCaT cell line, which is a multipotent cell line able to differentiate towards different phenotypes under the action of biological factors, has been evaluated with in vitro studies and quantified by colormetric assays. These findings indicate that the HDPE/BCP hybrid plates are biocompatible and non-toxic

  15. [Recent advance in research for myasthenia gravis, in relation to various antibodies affecting synaptic structure and function].

    Science.gov (United States)

    Takamori, Masaharu

    2009-11-01

    Autoantibodies impair acetylcholine receptor (AChR) in myasthenia gravis (MG) and P/Q-type voltage-gated calcium channel (VGCC) in Lambert-Eaton myasthenic syndrome (LEMS). (1) Some of MG and LEMS patients are "seronegative" for respective antibodies or modified by antibodies that recognize other proteins than AChR and VGCC such as MuSK, AChR allosteric site, membrane Na+ channel and ryanodine receptor-1 (RyR1) in MG, and synaptotagmin-1 in LEMS. (2) Autoimmune responses affect the proteins participating in the mechanisms to compensate for synaptic disorders on the basis of presynaptic Ca2+ homeostasis provided by VGCC and non-VGCC (receptor-operated TRPCs): they act as enhancers of Ca(2+) -mediated ACh release via phospholipase C signaling pathways including M1-type presynaptic muscarinic AChR, neurotrophin receptor (TrkB), and fast-mode of synaptic vesicle recycling. (3) The pathophysiology contributive to contractile fatigue in MG includes RyR1 and also TRPC3. The TRPC3 also forms a complex with STIM1 and Orail to make up for Ca2+ after sarcoplasmic Ca2+ release. The prevalent detection of anti-TRPC3 antibodies in MG with thymoma could affect muscle contractile machineries in addition to anti-RyR1-induced affection. (4) When one faces "seronegative" MG, one should be cautious to conformation-specific antibodies and also congenital myasthenic syndromes. PMID:20030211

  16. Short-term versus long-term water maze training effects on hippocampal neuronal synaptic plasticity in a rat model of senile dementia

    Institute of Scientific and Technical Information of China (English)

    Guogui Li

    2008-01-01

    BACKGROUND: Changes in synaptic plasticity might underlie senile dementia, and might be the neurobiological basis for learning and memory dysfunctions in patients with Alzheimer's Disease. OBJECTIVE: To investigate the effects of water maze training on hippocampal neuronal synaptic plasticity in rats with senile dementia, and to compare changes in synaptic plasticity between short- and long-term water maze training sessions.DESIGN, TIME AND SETTING: A randomized, controlled, neuromorphological observation with animal models of senile dementia was performed at the laboratory of College of Pharmacy, Chongqing Medical University between November 2006 and April 2007.MATERIALS: Fifty male, Sprague Dawley rats were randomized into five groups, with 10 rats per group: model, control, sham-operated, short-term water maze training, and long-term water maze training. METHODS: In the model group, senile dementia was induced by fimbria-fornix lesion method. The control rats remained untreated. In the sham-operated group, water maze training was performed without fimbria-fornix lesion induction. Rats from the short-term water maze training group underwent 20-day water maze training from day 26 after fimbria-fornix lesion induction. The long-term water maze training group underwent 40-day water maze training beginning at day 6 following fimbria-fornix lesion induction. Beginning at day 41, each group underwent 5-day spatial learning and memory training. MAIN OUTCOME MEASURES: Following experimentation, the morphological parameters of synapses, including synaptic numerical density, synaptic surface density, and the average synapse size were stereologically measured. Through the use of an electron microscope, synaptic morphological changes in the hippocampai CA3 region were observed.RESULTS: Compared with the control group, synaptic numerical and surface densities were significantly decreased in the model group (P < 0.01). Synaptic numerical and surface densities significantly

  17. Early pre- and postsynaptic calcium signaling abnormalities mask underlying synaptic depression in presymptomatic Alzheimer’s disease mice

    Science.gov (United States)

    Chakroborty, Shreaya; Kim, Joyce; Schneider, Corinne; Jacobson, Christopher; Molgó, Jordi; Stutzmann, Grace E.

    2012-01-01

    Alzheimer’s disease (AD)-linked presenilin mutations result in pronounced endoplasmic reticulum (ER) calcium disruptions that occur prior to detectable histopathology and cognitive deficits. More subtly, these early AD-linked calcium alterations also reset neurophysiological homeostasis, such that calcium-dependent pre- and postsynaptic signaling appear functionally normal yet are actually operating under aberrant calcium signaling systems. In these 3xTg-AD mouse brains, upregulated RyR activity is associated with a shift towards synaptic depression, likely through a reduction in presynaptic vesicle stores and increased postsynaptic outward currents through SK2 channels. The deviant RyR-calcium involvement in the 3xTg-AD mice also compensates for an intrinsic predisposition for hippocampal LTD and reduced LTP. In this study we detail the impact of disrupted ryanodine receptor (RyR)-mediated calcium stores on synaptic transmission properties, long term depression (LTD) and calcium-activated membrane channels of hippocampal CA1 pyramidal neurons in presymptomatic 3xTg-AD mice. Using electrophysiological recordings in young 3xTg-AD and NonTg hippocampal slices, we show that increased RyR-evoked calcium release in 3xTg-AD mice ‘normalizes’ an altered synaptic transmission system operating under a shifted homeostatic state that is not present in NonTg mice. In the process, we uncover compensatory signaling mechanisms recruited early in the disease process which counterbalance the disrupted RyR-calcium dynamics, namely increases in presynaptic spontaneous vesicle release, altered probability of vesicle release, and upregulated postsynaptic SK channel activity. As AD is increasingly recognized as a ‘synaptic disease’, calcium-mediated signaling alterations may serve as a proximal trigger for the synaptic degradation driving the cognitive loss in AD. PMID:22699914

  18. Differential Conditioning of Associative Synaptic Enhancement in Hippocampal Brain Slices

    Science.gov (United States)

    Kelso, Stephen R.; Brown, Thomas H.

    1986-04-01

    An electrophysiological stimulation paradigm similar to one that produces Pavlovian conditioning was applied to synaptic inputs to pyramidal neurons of hippocampal brain slices. Persistent synaptic enhancement was induced in one of two weak synaptic inputs by pairing high-frequency electrical stimulation of the weak input with stimulation of a third, stronger input to the same region. Forward (temporally overlapping) but not backward (temporally separate) pairings caused this enhancement. Thus hippocampal synapses in vitro can undergo the conditional and selective type of associative modification that could provide the substrate for some of the mnemonic functions in which the hippocampus is thought to participate.

  19. Spikes Synchronization in Neural Networks with Synaptic Plasticity

    CERN Document Server

    Borges, Rafael R; Batista, Antonio M; Caldas, Iberê L; Borges, Fernando S; Lameu, Ewandson L

    2015-01-01

    In this paper, we investigated the neural spikes synchronisation in a neural network with synaptic plasticity and external perturbation. In the simulations the neural dynamics is described by the Hodgkin Huxley model considering chemical synapses (excitatory) among neurons. According to neural spikes synchronisation is expected that a perturbation produce non synchronised regimes. However, in the literature there are works showing that the combination of synaptic plasticity and external perturbation may generate synchronised regime. This article describes the effect of the synaptic plasticity on the synchronisation, where we consider a perturbation with a uniform distribution. This study is relevant to researches of neural disorders control.

  20. A Voltage Mode Memristor Bridge Synaptic Circuit with Memristor Emulators

    Directory of Open Access Journals (Sweden)

    Leon Chua

    2012-03-01

    Full Text Available A memristor bridge neural circuit which is able to perform signed synaptic weighting was proposed in our previous study, where the synaptic operation was verified via software simulation of the mathematical model of the HP memristor. This study is an extension of the previous work advancing toward the circuit implementation where the architecture of the memristor bridge synapse is built with memristor emulator circuits. In addition, a simple neural network which performs both synaptic weighting and summation is built by combining memristor emulators-based synapses and differential amplifier circuits. The feasibility of the memristor bridge neural circuit is verified via SPICE simulations.

  1. Brain-derived neurotrophic factor (BDNF)-induced mitochondrial motility arrest and presynaptic docking contribute to BDNF-enhanced synaptic transmission.

    Science.gov (United States)

    Su, Bo; Ji, Yun-Song; Sun, Xu-lu; Liu, Xiang-Hua; Chen, Zhe-Yu

    2014-01-17

    Appropriate mitochondrial transport and distribution are essential for neurons because of the high energy and Ca(2+) buffering requirements at synapses. Brain-derived neurotrophic factor (BDNF) plays an essential role in regulating synaptic transmission and plasticity. However, whether and how BDNF can regulate mitochondrial transport and distribution are still unclear. Here, we find that in cultured hippocampal neurons, application of BDNF for 15 min decreased the percentage of moving mitochondria in axons, a process dependent on the activation of the TrkB receptor and its downstream PI3K and phospholipase-Cγ signaling pathways. Moreover, the BDNF-induced mitochondrial stopping requires the activation of transient receptor potential canonical 3 and 6 (TRPC3 and TRPC6) channels and elevated intracellular Ca(2+) levels. The Ca(2+) sensor Miro1 plays an important role in this process. Finally, the BDNF-induced mitochondrial stopping leads to the accumulation of more mitochondria at presynaptic sites. Mutant Miro1 lacking the ability to bind Ca(2+) prevents BDNF-induced mitochondrial presynaptic accumulation and synaptic transmission, suggesting that Miro1-mediated mitochondrial motility is involved in BDNF-induced mitochondrial presynaptic docking and neurotransmission. Together, these data suggest that mitochondrial transport and distribution play essential roles in BDNF-mediated synaptic transmission.

  2. Brain region specific pre-synaptic and post-synaptic degeneration are early components of neuropathology in prion disease.

    Directory of Open Access Journals (Sweden)

    Zuzana Šišková

    Full Text Available Synaptic abnormalities, one of the key features of prion disease pathogenesis, gives rise to functional deficits and contributes to the devastating clinical outcome. The synaptic compartment is the first to succumb in several neurodegenerative diseases linked with protein misfolding but the mechanisms underpinning this are poorly defined. In our current study we document that a focal intrahippocampal injection of the mouse-adapted 22L scrapie strain produces a complex, region-specific pathology in the brain. Our findings reveal that early synaptic changes in the stratum radiatum of the hippocampus, identical to those observed with the ME7 strain, occur when 22L strain is introduced into the hippocampus. The pathology was defined by degenerating Type I pre-synaptic elements progressively enveloped by the post-synaptic density of the dendritic spine. In contrast, the pathology in the cerebellum suggested that dendritic disintegration rather than pre-synaptic abnormalities dominate the early degenerative changes associated with the Purkinje cells. Indeed, both of the major synaptic inputs into the cerebellum, which arise from the parallel and climbing fibers, remained intact even at late stage disease. Immunolabeling with pathway selective antibodies reinforced these findings. These observations demonstrate that neuronal vulnerability to pathological protein misfolding is strongly dependent on the structure and function of the target neurons.

  3. ATP-ases of synaptic plasma membranes in striatum: enzymatic systems for synapses functionality by in vivo administration of L-acetylcarnitine in relation to Parkinson's Disease.

    Science.gov (United States)

    Villa, R F; Ferrari, F; Gorini, A

    2013-09-17

    The maximum rate (Vmax) of some enzymatic activities related to energy consumption was evaluated in synaptic plasma membranes from rat brain striatum, the synaptic energy state being a crucial factor in neurodegenerative diseases etiopathogenesis. Two types of synaptic plasma membranes were isolated from rats subjected to in vivo treatment with L-acetylcarnitine at two different doses (30 and 60 mg × kg(-1) i.p., 28 days, 5 days/week). The following enzyme activities were evaluated: acetylcholinesterase (AChE); Na(+), K(+), Mg(2+)-ATP-ase; ouabain insensitive Mg(2+)-ATP-ase; Na(+), K(+)-ATP-ase; direct Mg(2+)-ATP-ase; Ca(2+), Mg(2+)-ATP-ase; and low- and high-affinity Ca(2+)-ATP-ase. In control (vehicle-treated) animals, enzymatic activities are differently expressed in synaptic plasma membranes type I (SPM1) with respect to synaptic plasma membranes type II (SPM2), the evaluated enzymatic activities being higher in SPM2. Subchronic treatment with L-acetylcarnitine decreased AChE on SPM1 and SPM2 at the dose of 30 mg × kg(-1). Pharmacological treatment decreased ouabain insensitive Mg(2+)-ATP-ase activity and high affinity Ca(2+)-ATP-ase activity at the doses of 30 and 60 mg × kg(-1) respectively on SPM1, while it decreased Na(+), K(+)-ATP-ase, direct Mg(2+)-ATP-ase and Ca(2+), Mg(2+)-ATP-ase activities at the dose of 30 mg × kg(-1) on SPM2. These results suggest that the sensitivity to drug treatment is different between these two populations of synaptic plasma membranes from the striatum, confirming the micro-heterogeneity of these subfractions, possessing different metabolic machinery with respect to energy consumption and utilization and the regional selective effect of L-acetylcarnitine on cerebral tissue, depending on the considered area. The drug potential effect at the synaptic level in Parkinson's Disease neuroprotection is also discussed with respect to acetylcholine and energy metabolism.

  4. Characterizing synaptic protein development in human visual cortex enables alignment of synaptic age with rat visual cortex

    Directory of Open Access Journals (Sweden)

    Joshua G.A Pinto

    2015-02-01

    Full Text Available Although many potential neuroplasticity based therapies have been developed in the lab, few have translated into established clinical treatments for human neurologic or neuropsychiatric diseases. Animal models, especially of the visual system, have shaped our understanding of neuroplasticity by characterizing the mechanisms that promote neural changes and defining timing of the sensitive period. The lack of knowledge about development of synaptic plasticity mechanisms in human cortex, and about alignment of synaptic age between animals and humans, has limited translation of neuroplasticity therapies. In this study, we quantified expression of a set of highly conserved pre- and post-synaptic proteins (Synapsin, Synaptophysin, PSD-95, Gephyrin and found that synaptic development in human primary visual cortex continues into late childhood. Indeed, this is many years longer than suggested by neuroanatomical studies and points to a prolonged sensitive period for plasticity in human sensory cortex. In addition, during childhood we found waves of inter-individual variability that are different for the 4 proteins and include a stage during early development (<1 year when only Gephyrin has high inter-individual variability. We also found that pre- and post-synaptic protein balances develop quickly, suggesting that maturation of certain synaptic functions happens within the first year or two of life. A multidimensional analysis (principle component analysis showed that most of the variance was captured by the sum of the 4 synaptic proteins. We used that sum to compare development of human and rat visual cortex and identified a simple linear equation that provides robust alignment of synaptic age between humans and rats. Alignment of synaptic ages is important for age-appropriate targeting and effective translation of neuroplasticity therapies from the lab to the clinic.

  5. Hippocampal CA1 Ripples as Inhibitory Transients.

    Science.gov (United States)

    Malerba, Paola; Krishnan, Giri P; Fellous, Jean-Marc; Bazhenov, Maxim

    2016-04-01

    Memories are stored and consolidated as a result of a dialogue between the hippocampus and cortex during sleep. Neurons active during behavior reactivate in both structures during sleep, in conjunction with characteristic brain oscillations that may form the neural substrate of memory consolidation. In the hippocampus, replay occurs within sharp wave-ripples: short bouts of high-frequency activity in area CA1 caused by excitatory activation from area CA3. In this work, we develop a computational model of ripple generation, motivated by in vivo rat data showing that ripples have a broad frequency distribution, exponential inter-arrival times and yet highly non-variable durations. Our study predicts that ripples are not persistent oscillations but result from a transient network behavior, induced by input from CA3, in which the high frequency synchronous firing of perisomatic interneurons does not depend on the time scale of synaptic inhibition. We found that noise-induced loss of synchrony among CA1 interneurons dynamically constrains individual ripple duration. Our study proposes a novel mechanism of hippocampal ripple generation consistent with a broad range of experimental data, and highlights the role of noise in regulating the duration of input-driven oscillatory spiking in an inhibitory network. PMID:27093059

  6. Hippocampal CA1 Ripples as Inhibitory Transients.

    Directory of Open Access Journals (Sweden)

    Paola Malerba

    2016-04-01

    Full Text Available Memories are stored and consolidated as a result of a dialogue between the hippocampus and cortex during sleep. Neurons active during behavior reactivate in both structures during sleep, in conjunction with characteristic brain oscillations that may form the neural substrate of memory consolidation. In the hippocampus, replay occurs within sharp wave-ripples: short bouts of high-frequency activity in area CA1 caused by excitatory activation from area CA3. In this work, we develop a computational model of ripple generation, motivated by in vivo rat data showing that ripples have a broad frequency distribution, exponential inter-arrival times and yet highly non-variable durations. Our study predicts that ripples are not persistent oscillations but result from a transient network behavior, induced by input from CA3, in which the high frequency synchronous firing of perisomatic interneurons does not depend on the time scale of synaptic inhibition. We found that noise-induced loss of synchrony among CA1 interneurons dynamically constrains individual ripple duration. Our study proposes a novel mechanism of hippocampal ripple generation consistent with a broad range of experimental data, and highlights the role of noise in regulating the duration of input-driven oscillatory spiking in an inhibitory network.

  7. ZD7288, a selective hyperpolarization-activated cyclic nucleotide-gated channel blocker, inhibits hippocampal synaptic plasticity

    Institute of Scientific and Technical Information of China (English)

    Xiao-xue Zhang; Xiao-chun Min; Xu-lin Xu; Min Zheng; Lian-jun Guo

    2016-01-01

    The selective hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blocker 4-(N-ethyl-N-phenylamino)-1,2-dimeth-yl-6-(methylamino) pyrimidinium chloride (ZD7288) blocks the induction of long-term potentiation in the perforant path–CA3 region in rat hippocampusin vivo. To explore the mechanisms underlying the action of ZD7288, we recorded excitatory postsynaptic potentials in perforant path–CA3 synapses in male Sprague-Dawley rats. We measured glutamate content in the hippocampus and in cultured hip-pocampal neurons using high performance liquid chromatography, and determined intracellular Ca2+ concentration ([Ca2+]i) using Fura-2. ZD7288 inhibited the induction and maintenance of long-term potentiation, and these effects were mirrored by the nonspeciifc HCN channel blocker cesium. ZD7288 also decreased glutamate release in hippocampal tissue and in cultured hippocampal neurons. Further-more, ZD7288 attenuated glutamate-induced rises in [Ca2+]i in a concentration-dependent manner and reversed 8-Br-cAMP-mediated facilitation of these glutamate-induced [Ca2+]i rises. Our results suggest that ZD7288 inhibits hippocampal synaptic plasticity both gluta-mate release and resultant [Ca2+]i increases in rat hippocampal neurons.

  8. Caenorhabditis elegans intersectin: a synaptic protein regulating neurotransmission

    DEFF Research Database (Denmark)

    Rose, Simon; Malabarba, Maria Grazia; Krag, Claudia;

    2007-01-01

    Intersectin is a multifunctional protein that interacts with components of the endocytic and exocytic pathways, and it is also involved in the control of actin dynamics. Drosophila intersectin is required for viability, synaptic development, and synaptic vesicle recycling. Here, we report...... phenotype, under physiological conditions. However, they display aldicarb-hypersensitivity, compatible with a negative regulatory role of ITSN-1 on neurotransmission. ITSN-1 physically interacts with dynamin and EHS-1, two proteins involved in synaptic vesicle recycling. We have previously shown that EHS-1...... is a positive modulator of synaptic vesicle recycling in the nematode, likely through modulation of dynamin or dynamin-controlled pathways. Here, we show that ITSN-1 and EHS-1 have opposite effects on aldicarb sensitivity, and on dynamin-dependent phenotypes. Thus, the sum of our results identifies dynamin...

  9. Proteomic Analysis of Unbounded Cellular Compartments: Synaptic Clefts.

    Science.gov (United States)

    Loh, Ken H; Stawski, Philipp S; Draycott, Austin S; Udeshi, Namrata D; Lehrman, Emily K; Wilton, Daniel K; Svinkina, Tanya; Deerinck, Thomas J; Ellisman, Mark H; Stevens, Beth; Carr, Steven A; Ting, Alice Y

    2016-08-25

    Cellular compartments that cannot be biochemically isolated are challenging to characterize. Here we demonstrate the proteomic characterization of the synaptic clefts that exist at both excitatory and inhibitory synapses. Normal brain function relies on the careful balance of these opposing neural connections, and understanding how this balance is achieved relies on knowledge of their protein compositions. Using a spatially restricted enzymatic tagging strategy, we mapped the proteomes of two of the most common excitatory and inhibitory synaptic clefts in living neurons. These proteomes reveal dozens of synaptic candidates and assign numerous known synaptic proteins to a specific cleft type. The molecular differentiation of each cleft allowed us to identify Mdga2 as a potential specificity factor influencing Neuroligin-2's recruitment of presynaptic neurotransmitters at inhibitory synapses. PMID:27565350

  10. Synaptic remodeling of neuronal circuits in early retinal degeneration

    Science.gov (United States)

    Soto, Florentina; Kerschensteiner, Daniel

    2015-01-01

    Photoreceptor degenerations are a major cause of blindness and among the most common forms of neurodegeneration in humans. Studies of mouse models revealed that synaptic dysfunction often precedes photoreceptor degeneration, and that abnormal synaptic input from photoreceptors to bipolar cells causes circuits in the inner retina to become hyperactive. Here, we provide a brief overview of frequently used mouse models of photoreceptor degenerations. We then discuss insights into circuit remodeling triggered by early synaptic dysfunction in the outer and hyperactivity in the inner retina. We discuss these insights in the context of other experimental manipulations of synaptic function and activity. Knowledge of the plasticity and early remodeling of retinal circuits will be critical for the design of successful vision rescue strategies. PMID:26500497

  11. Compatibility between itinerant synaptic receptors and stable postsynaptic structure

    CERN Document Server

    Sekimoto, Ken

    2009-01-01

    The density of synaptic receptors in front of presynaptic release sites is stabilized in the presence of scaffold proteins, but the receptors and scaffold molecules have local exchanges with characteristic times shorter than that of the receptor-scaffold assembly. We propose a mesoscopic model to account for the regulation of the local density of receptors as quasiequilibrium. It is based on two zones (synaptic and extrasynaptic) and multi-layer (membrane, sub-membrane and cytoplasmic) topological organization. The model includes the balance of chemical potentials associated with the receptor and scaffold protein concentrations in the various compartments. The model shows highly cooperative behavior including a "phase change" resulting in the formation of well-defined post-synaptic domains. This study provides theoretical tools to approach the complex issue of synaptic stability at the synapse, where receptors are transiently trapped yet rapidly diffuse laterally on the plasma membrane.

  12. Synaptic remodeling of neuronal circuits in early retinal degeneration

    Directory of Open Access Journals (Sweden)

    Florentina eSoto

    2015-10-01

    Full Text Available Photoreceptor degenerations are a major cause of blindness and among the most common forms of neurodegeneration in humans. Studies of mouse models revealed that synaptic dysfunction often precedes photoreceptor degeneration, and that abnormal synaptic input from photoreceptors to bipolar cells causes circuits in the inner retina to become hyperactive. Here, we provide a brief overview of frequently used mouse models of photoreceptor degenerations. We then discuss insights into circuit remodeling triggered by early synaptic dysfunction in the outer and hyperactivity in the inner retina. We discuss these insights in the context of other experimental manipulations of synaptic function and activity. Knowledge of the plasticity and early remodeling of retinal circuits will be critical for the design of successful vision rescue strategies.

  13. Corticosteroid Regulation of Synaptic Plasticity in the Hippocampus

    OpenAIRE

    Nicola Maggio; Menahem Segal

    2010-01-01

    Stress, via release of steroid hormones, has been shown to affect several cellular functions in the brain, including synaptic receptors and ion channels. As such, corticosteroids were reported to modulate plasticity, expressed as long-term changes in reactivity to afferent stimulation. The classical view of the effects of stress on synaptic plasticity and cognitive functions assumes an inverted U-shape curve, such that a low stress level facilitates and a high stress level (i.e., corticostero...

  14. Synaptic Contacts Enhance Cell-to-Cell Tau Pathology Propagation

    OpenAIRE

    Sara Calafate; Arjan Buist; Katarzyna Miskiewicz; Vinoy Vijayan; Guy Daneels; Bart de Strooper; Joris de Wit; Patrik Verstreken; Diederik Moechars

    2015-01-01

    Accumulation of insoluble Tau protein aggregates and stereotypical propagation of Tau pathology through the brain are common hallmarks of tauopathies, including Alzheimer’s disease (AD). Propagation of Tau pathology appears to occur along connected neurons, but whether synaptic contacts between neurons are facilitating propagation has not been demonstrated. Using quantitative in vitro models, we demonstrate that, in parallel to non-synaptic mechanisms, synapses, but not merely the close dista...

  15. Activity-dependent modulation of neural circuit synaptic connectivity

    OpenAIRE

    Tessier, Charles R.; Kendal Broadie

    2009-01-01

    In many nervous systems, the establishment of neural circuits is known to proceed via a two-stage process; 1) early, activity-independent wiring to produce a rough map characterized by excessive synaptic connections, and 2) subsequent, use-dependent pruning to eliminate inappropriate connections and reinforce maintained synapses. In invertebrates, however, evidence of the activity-dependent phase of synaptic refinement has been elusive, and the dogma has long been that invertebrate circ...

  16. Nonequivalent release sites govern synaptic depression.

    Science.gov (United States)

    Wen, Hua; McGinley, Matthew J; Mandel, Gail; Brehm, Paul

    2016-01-19

    Synaptic depression is prominent among synapses, but the underlying mechanisms remain uncertain. Here, we use paired patch clamp recording to study neuromuscular transmission between the caudal primary motor neuron and target skeletal muscle in zebrafish. This synapse has an unusually low number of release sites, all with high probabilities of release in response to low-frequency stimulation. During high-frequency stimulation, the synapse undergoes short-term depression and reaches steady-state levels of transmission that sustain the swimming behavior. To determine the release parameters underlying this steady state, we applied variance analysis. Our analysis revealed two functionally distinct subclasses of release sites differing by over 60-fold in rates of vesicle reloading. A slow reloading class requires seconds to recover and contributes to depression onset but not the steady-state transmission. By contrast, a fast reloading class recovers within tens of milliseconds and is solely responsible for steady-state transmission. Thus, in contrast to most current models that assign levels of steady-state depression to vesicle availability, our findings instead assign this function to nonuniform release site kinetics. The duality of active-site properties accounts for the highly nonlinear dependence of steady-state depression levels on frequency. PMID:26715759

  17. Synaptic failure: The achilles tendon of sphingolipidoses.

    Science.gov (United States)

    Cantuti-Castelvetri, Ludovico; Bongarzone, Ernesto R

    2016-11-01

    The presence of life-threatening neurological symptoms in more than two-thirds of lysosomal storage diseases (LSDs) underscores how vulnerable the nervous system is to lysosomal failure. Neurological dysfunction in LSDs has historically been attributed to the disruption of neuronal and glial homeostasis resulting from the progressive jamming of the endosomal/lysosomal pathway. In neurons, a dysfunctional endosomal-lysosomal system can elicit dire consequences. Given that neurons are largely postmitotic after birth, one can clearly understand that the inability of these cells to proliferate obliterates any possibility of diluting stored lysosomal material by means of cellular division. At its most advanced stage, this situation constitutes a terminal factor in neuronal life, resulting in cell death. However, synaptic deficits in the absence of classical neuronal cell death appear to be common features during the early stages in many LSDs, particularly sphingolipidoses. In essence, failure of synapses to convey their messages, even without major structural damage to the neuronal bodies, is a form of physiological death. This concept of dying-back neuropathology is highly relevant not only for understanding the dynamics of the neurological decline in these diseases, but, more importantly; it might also constitute an important target for molecular therapies to protect perhaps the "Achilles" point in the entire physiological architecture of the brain, thus avoiding an irreversible journey to neuronal demise. © 2016 Wiley Periodicals, Inc. PMID:27638588

  18. Intervertebral Disc Tissue Engineering with Natural Extracellular Matrix-Derived Biphasic Composite Scaffolds.

    Directory of Open Access Journals (Sweden)

    Baoshan Xu

    Full Text Available Tissue engineering has provided an alternative therapeutic possibility for degenerative disc diseases. However, we lack an ideal scaffold for IVD tissue engineering. The goal of this study is to fabricate a novel biomimetic biphasic scaffold for IVD tissue engineering and evaluate the feasibility of developing tissue-engineered IVD in vitro and in vivo. In present study we developed a novel integrated biphasic IVD scaffold using a simple freeze-drying and cross-linking technique of pig bone matrix gelatin (BMG for the outer annulus fibrosus (AF phase and pig acellular cartilage ECM (ACECM for the inner nucleus pulposus (NP phase. Histology and SEM results indicated no residual cells remaining in the scaffold that featured an interconnected porous microstructure (pore size of AF and NP phase 401.4 ± 13.1 μm and 231.6 ± 57.2 μm, respectively. PKH26-labeled AF and NP cells were seeded into the scaffold and cultured in vitro. SEM confirmed that seeded cells could anchor onto the scaffold. Live/dead staining showed that live cells (green fluorescence were distributed in the scaffold, with no dead cells (red fluorescence being found. The cell-scaffold constructs were implanted subcutaneously into nude mice and cultured for 6 weeks in vivo. IVD-like tissue formed in nude mice as confirmed by histology. Cells in hybrid constructs originated from PKH26-labeled cells, as confirmed by in vivo fluorescence imaging system. In conclusion, the study demonstrates the feasibility of developing a tissue-engineered IVD in vivo with a BMG- and ACECM-derived integrated AF-NP biphasic scaffold. As well, PKH26 fluorescent labeling with in vivo fluorescent imaging can be used to track cells and analyse cell--scaffold constructs in vivo.

  19. Lipase in biphasic alginate beads as a biocatalyst for esterification of butyric acid and butanol in aqueous media.

    Science.gov (United States)

    Ng, Choong Hey; Yang, Kun-Lin

    2016-01-01

    Esterification of organic acids and alcohols in aqueous media is very inefficient due to thermodynamic constraints. However, fermentation processes used to produce organic acids and alcohols are often conducted in aqueous media. To produce esters in aqueous media, biphasic alginate beads with immobilized lipase are developed for in situ esterification of butanol and butyric acid. The biphasic beads contain a solid matrix of calcium alginate and hexadecane together with 5 mg/mL of lipase as the biocatalyst. Hexadecane in the biphasic beads serves as an organic phase to facilitate the esterification reaction. Under optimized conditions, the beads are able to catalyze the production of 0.16 mmol of butyl butyrate from 0.5 mmol of butyric acid and 1.5 mmol of butanol. In contrast, when monophasic beads (without hexadecane) are used, only trace amount of butyl butyrate is produced. One main application of biphasic beads is in simultaneous fermentation and esterification (SFE) because the organic phase inside the beads is very stable and does not leach out into the culture medium. SFE is successfully conducted with an esterification yield of 6.32% using biphasic beads containing iso-octane even though the solvent is proven toxic to the butanol-producing Clostridium spp. PMID:26672465

  20. Imaging synaptic density in the living human brain.

    Science.gov (United States)

    Finnema, Sjoerd J; Nabulsi, Nabeel B; Eid, Tore; Detyniecki, Kamil; Lin, Shu-Fei; Chen, Ming-Kai; Dhaher, Roni; Matuskey, David; Baum, Evan; Holden, Daniel; Spencer, Dennis D; Mercier, Joël; Hannestad, Jonas; Huang, Yiyun; Carson, Richard E

    2016-07-20

    Chemical synapses are the predominant neuron-to-neuron contact in the central nervous system. Presynaptic boutons of neurons contain hundreds of vesicles filled with neurotransmitters, the diffusible signaling chemicals. Changes in the number of synapses are associated with numerous brain disorders, including Alzheimer's disease and epilepsy. However, all current approaches for measuring synaptic density in humans require brain tissue from autopsy or surgical resection. We report the use of the synaptic vesicle glycoprotein 2A (SV2A) radioligand [(11)C]UCB-J combined with positron emission tomography (PET) to quantify synaptic density in the living human brain. Validation studies in a baboon confirmed that SV2A is an alternative synaptic density marker to synaptophysin. First-in-human PET studies demonstrated that [(11)C]UCB-J had excellent imaging properties. Finally, we confirmed that PET imaging of SV2A was sensitive to synaptic loss in patients with temporal lobe epilepsy. Thus, [(11)C]UCB-J PET imaging is a promising approach for in vivo quantification of synaptic density with several potential applications in diagnosis and therapeutic monitoring of neurological and psychiatric disorders. PMID:27440727

  1. The influence of synaptic weight distribution on neuronal population dynamics.

    Directory of Open Access Journals (Sweden)

    Ramakrishnan Iyer

    2013-10-01

    Full Text Available The manner in which different distributions of synaptic weights onto cortical neurons shape their spiking activity remains open. To characterize a homogeneous neuronal population, we use the master equation for generalized leaky integrate-and-fire neurons with shot-noise synapses. We develop fast semi-analytic numerical methods to solve this equation for either current or conductance synapses, with and without synaptic depression. We show that its solutions match simulations of equivalent neuronal networks better than those of the Fokker-Planck equation and we compute bounds on the network response to non-instantaneous synapses. We apply these methods to study different synaptic weight distributions in feed-forward networks. We characterize the synaptic amplitude distributions using a set of measures, called tail weight numbers, designed to quantify the preponderance of very strong synapses. Even if synaptic amplitude distributions are equated for both the total current and average synaptic weight, distributions with sparse but strong synapses produce higher responses for small inputs, leading to a larger operating range. Furthermore, despite their small number, such synapses enable the network to respond faster and with more stability in the face of external fluctuations.

  2. Cerebellar Synaptic Plasticity and the Credit Assignment Problem.

    Science.gov (United States)

    Jörntell, Henrik

    2016-04-01

    The mechanism by which a learnt synaptic weight change can contribute to learning or adaptation of brain function is a type of credit assignment problem, which is a key issue for many parts of the brain. In the cerebellum, detailed knowledge not only of the local circuitry connectivity but also of the topography of different sources of afferent/external information makes this problem particularly tractable. In addition, multiple forms of synaptic plasticity and their general rules of induction have been identified. In this review, we will discuss the possible roles of synaptic and cellular plasticity at specific locations in contributing to behavioral changes. Focus will be on the parts of the cerebellum that are devoted to limb control, which constitute a large proportion of the cortex and where the knowledge of the external connectivity is particularly well known. From this perspective, a number of sites of synaptic plasticity appear to primarily have the function of balancing the overall level of activity in the cerebellar circuitry, whereas the locations at which synaptic plasticity leads to functional changes in terms of limb control are more limited. Specifically, the postsynaptic forms of long-term potentiation (LTP) and long-term depression (LTD) at the parallel fiber synapses made on interneurons and Purkinje cells, respectively, are the types of plasticity that mediate the widest associative capacity and the tightest link between the synaptic change and the external functions that are to be controlled. PMID:25417189

  3. A Galerkin least-square stabilisation technique for hyperelastic biphasic soft tissue

    CERN Document Server

    Vignollet, Julien; Kaczmarczyk, Lukasz

    2011-01-01

    An hyperelastic biphasic model is presented. For slow-draining problems (permeability less than 1\\times10-2 mm4 N-1 s-1), numerical instabilities in the form of non-physical oscillations in the pressure field are observed in 3D problems using tetrahedral Taylor-Hood finite elements. As an alternative to considerable mesh refinement, a Galerkin least-square stabilization framework is proposed. This technique drastically reduces the pressure discrepancies and prevents these oscillations from propagating towards the centre of the medium. The performance and robustness of this technique are demonstrated on a 3D numerical example.

  4. Use of Biphasic Continuous Positive Airway Pressure in Premature Infant with Cleft Lip–Cleft Palate

    Science.gov (United States)

    George, Lovya; Jain, Sunil K.

    2015-01-01

    Preterm infants (PIs) often require respiratory support due to surfactant deficiency. Early weaning from mechanical ventilation to noninvasive respiratory support decreases ventilation-associated irreversible lung damage. This wean is particularly challenging in PIs with cleft lip and cleft palate due to anatomical difficulties encountered in maintaining an adequate seal for positive pressure ventilation. PI with a cleft lip and palate often fail noninvasive respiratory support and require continued intubation and mechanical ventilation. We are presenting the first case report of a PI with cleft lip and palate who was managed by biphasic nasal continuous positive airway pressure. PMID:26495158

  5. Use of Biphasic Continuous Positive Airway Pressure in Premature Infant with Cleft Lip–Cleft Palate

    Directory of Open Access Journals (Sweden)

    Lovya George

    2015-10-01

    Full Text Available Preterm infants (PIs often require respiratory support due to surfactant deficiency. Early weaning from mechanical ventilation to noninvasive respiratory support decreases ventilation-associated irreversible lung damage. This wean is particularly challenging in PIs with cleft lip and cleft palate due to anatomical difficulties encountered in maintaining an adequate seal for positive pressure ventilation. PI with a cleft lip and palate often fail noninvasive respiratory support and require continued intubation and mechanical ventilation. We are presenting the first case report of a PI with cleft lip and palate who was managed by biphasic nasal continuous positive airway pressure.

  6. Extraction of Biomolecules Using Phosphonium-Based Ionic Liquids + K3PO4 Aqueous Biphasic Systems

    OpenAIRE

    Louros, Cláudia L. S.; Cláudio, Ana Filipa M.; Neves, Catarina M. S. S.; Freire, Mara G.; Marrucho, Isabel M.; Jérôme Pauly; Coutinho, João A. P.

    2010-01-01

    Aqueous biphasic systems (ABS) provide an alternative and efficient approach for the extraction, recovery and purification of biomolecules through their partitioning between two liquid aqueous phases. In this work, the ability of hydrophilic phosphonium-based ionic liquids (ILs) to form ABS with aqueous K3PO4 solutions was evaluated for the first time. Ternary phase diagrams, and respective tie-lines and tie-lines length, formed by distinct phosphonium-based ILs, water, and K3PO4 at 298 K, we...

  7. Biphasic Dose Response in Low Level Light Therapy – An Update

    OpenAIRE

    Huang, Ying-Ying; Sharma, Sulbha K.; Carroll, James; Hamblin, Michael R.

    2011-01-01

    Low-level laser (light) therapy (LLLT) has been known since 1967 but still remains controversial due to incomplete understanding of the basic mechanisms and the selection of inappropriate dosimetric parameters that led to negative studies. The biphasic dose-response or Arndt-Schulz curve in LLLT has been shown both in vitro studies and in animal experiments. This review will provide an update to our previous (Huang et al. 2009) coverage of this topic. In vitro mediators of LLLT such as adenos...

  8. Use of Biphasic Continuous Positive Airway Pressure in Premature Infant with Cleft Lip-Cleft Palate.

    Science.gov (United States)

    George, Lovya; Jain, Sunil K

    2015-10-01

    Preterm infants (PIs) often require respiratory support due to surfactant deficiency. Early weaning from mechanical ventilation to noninvasive respiratory support decreases ventilation-associated irreversible lung damage. This wean is particularly challenging in PIs with cleft lip and cleft palate due to anatomical difficulties encountered in maintaining an adequate seal for positive pressure ventilation. PI with a cleft lip and palate often fail noninvasive respiratory support and require continued intubation and mechanical ventilation. We are presenting the first case report of a PI with cleft lip and palate who was managed by biphasic nasal continuous positive airway pressure. PMID:26495158

  9. Steroid biotransformations in biphasic systems with Yarrowia lipolytica expressing human liver cytochrome P450 genes

    Directory of Open Access Journals (Sweden)

    Braun Andreas

    2012-08-01

    Full Text Available Abstract Background Yarrowia lipolytica efficiently metabolizes and assimilates hydrophobic compounds such as n-alkanes and fatty acids. Efficient substrate uptake is enabled by naturally secreted emulsifiers and a modified cell surface hydrophobicity and protrusions formed by this yeast. We were examining the potential of recombinant Y. lipolytica as a biocatalyst for the oxidation of hardly soluble hydrophobic steroids. Furthermore, two-liquid biphasic culture systems were evaluated to increase substrate availability. While cells, together with water soluble nutrients, are maintained in the aqueous phase, substrates and most of the products are contained in a second water-immiscible organic solvent phase. Results For the first time we have co-expressed the human cytochromes P450 2D6 and 3A4 genes in Y. lipolytica together with human cytochrome P450 reductase (hCPR or Y. lipolytica cytochrome P450 reductase (YlCPR. These whole-cell biocatalysts were used for the conversion of poorly soluble steroids in biphasic systems. Employing a biphasic system with the organic solvent and Y. lipolytica carbon source ethyl oleate for the whole-cell bioconversion of progesterone, the initial specific hydroxylation rate in a 1.5 L stirred tank bioreactor was further increased 2-fold. Furthermore, the product formation was significantly prolonged as compared to the aqueous system. Co-expression of the human CPR gene led to a 4-10-fold higher specific activity, compared to the co-overexpression of the native Y. lipolytica CPR gene. Multicopy transformants showed a 50-70-fold increase of activity as compared to single copy strains. Conclusions Alkane-assimilating yeast Y. lipolytica, coupled with the described expression strategies, demonstrated its high potential for biotransformations of hydrophobic substrates in two-liquid biphasic systems. Especially organic solvents which can be efficiently taken up and/or metabolized by the cell might enable more

  10. Activated microglia in acute encephalopathy with biphasic seizures and late reduced diffusion.

    Science.gov (United States)

    Fujita, Yuji; Takanashi, Jun-Ichi; Takei, Haruka; Ota, Setsuo; Fujii, Katsunori; Sakuma, Hiroshi; Hayashi, Masaharu

    2016-07-15

    Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is the most common subtype of infectious pediatric encephalopathy in Japan. The exact pathogenesis of and the best therapeutic strategy for AESD are uncertain. We firstly performed a brain biopsy in a 2-year-old boy with AESD associated with RS viral infection, which revealed activated ameoboid microglia accumulation around degenerated neuron, and astrogliosis in the affected cortex. Glutamate released from activated microglia may play an important role in the pathogenesis of AESD, which is compatible with the previous report of magnetic resonance spectroscopy showing elevated glutamate. PMID:27288783

  11. A Novel Ionic Liquid/water Biphasic System for the Preparation of Oximes

    Institute of Scientific and Technical Information of China (English)

    Hui Mou LUO; Yi Qun LI; Wen Jie ZHENG

    2005-01-01

    A variety of carbonyl compounds can be converted into oximes efficiently and conveniently in a novel ionic liquid/water bi-phasic system in the presence of sodium bicarbonate at ambient temperature. The ionic liquid 1-butyl-3-methyl imidazolium hexafluorophosphate [bmim]PF6 is immiscible with water or diethyl ether and can be easily recycled for reuse without noticeable droping in activity after separation of the products. The protocol is rapid, the yields are excellent, the method is simple and the ionic liquid can be reused.

  12. Evidence for chelatable zinc in the extracellular space of the hippocampus, but little evidence for synaptic release of Zn.

    Science.gov (United States)

    Kay, Alan R

    2003-07-30

    Zinc colocalizes with glutamate in the synaptic vesicles of certain glutamatergic vesicles in the mammalian brain. Here, I introduce a method for detecting Zn in the extracellular space of brain slices and another method for detecting the passage of Zn out of the slice. In both cases, the fluorimetric Zn probe FluoZin-3 is used in conjunction with a slow Zn chelator, Ca-EDTA, to reduce background fluorescence. In addition, a new Zn chelator, ethylenediiminodi-2-pentanedioic acid, with little affinity for Ca or Mg is introduced. These tools are then used to show that little Zn (approximately 2 nm) is released during the course of synaptic transmission into the extracellular space. However, when hippocampal slices are subjected to a high potassium stimulus (50 mM) combined with an increase in osmolarity, Zn is externalized in the Timm's-stained areas (approximately 6 nm). This stimulus also leads to even greater Zn elevations in area CA1 that is only weakly stained by the Timm's method. Nevertheless, even under these conditions, little if any Zn makes its way out of the slices. I present evidence for a layer of Zn in the extracellular space that maps onto the Timm's stained region of the hippocampus. This Zn veneer appears to be loosely associated with molecules in the extracellular space and may be the raison d'être for vesicular Zn.

  13. The origin of glutamatergic synaptic inputs controls synaptic plasticity and its modulation by alcohol in mice nucleus accumbens

    OpenAIRE

    Ji, Xincai; Saha, Sucharita; Martin, Gilles E.

    2015-01-01

    It is widely accepted that long-lasting changes of synaptic strength in the nucleus accumbens (NAc), a brain region involved in drug reward, mediate acute and chronic effects of alcohol. However, our understanding of the mechanisms underlying the effects of alcohol on synaptic plasticity is limited by the fact that the NAc receives glutamatergic inputs from distinct brain regions (e.g., the prefrontal cortex (PFCx), the amygdala and the hippocampus), each region providing different informatio...

  14. Shisa6 traps AMPA receptors at postsynaptic sites and prevents their desensitization during synaptic activity.

    Science.gov (United States)

    Klaassen, Remco V; Stroeder, Jasper; Coussen, Françoise; Hafner, Anne-Sophie; Petersen, Jennifer D; Renancio, Cedric; Schmitz, Leanne J M; Normand, Elisabeth; Lodder, Johannes C; Rotaru, Diana C; Rao-Ruiz, Priyanka; Spijker, Sabine; Mansvelder, Huibert D; Choquet, Daniel; Smit, August B

    2016-03-02

    Trafficking and biophysical properties of AMPA receptors (AMPARs) in the brain depend on interactions with associated proteins. We identify Shisa6, a single transmembrane protein, as a stable and directly interacting bona fide AMPAR auxiliary subunit. Shisa6 is enriched at hippocampal postsynaptic membranes and co-localizes with AMPARs. The Shisa6 C-terminus harbours a PDZ domain ligand that binds to PSD-95, constraining mobility of AMPARs in the plasma membrane and confining them to postsynaptic densities. Shisa6 expressed in HEK293 cells alters GluA1- and GluA2-mediated currents by prolonging decay times and decreasing the extent of AMPAR desensitization, while slowing the rate of recovery from desensitization. Using gene deletion, we show that Shisa6 increases rise and decay times of hippocampal CA1 miniature excitatory postsynaptic currents (mEPSCs). Shisa6-containing AMPARs show prominent sustained currents, indicating protection from full desensitization. Accordingly, Shisa6 prevents synaptically trapped AMPARs from depression at high-frequency synaptic transmission.

  15. Synaptic Remodeling Generates Synchronous Oscillations in the Degenerated Outer Mouse Retina

    Directory of Open Access Journals (Sweden)

    Wadood eHaq

    2014-09-01

    Full Text Available During neuronal degenerative diseases, neuronal microcircuits undergo severe structural alterations, leading to remodeling of synaptic connectivity. The functional consequences of such remodeling are mostly unknown. For instance, in mutant rd1 mouse retina, a common model for Retinitis Pigmentosa, rod bipolar cells (RBCs establish contacts with remnant cone photoreceptors (cones as a consequence of rod photoreceptor cell death and the resulting lack of presynaptic input. To assess the functional connectivity in the remodeled, light-insensitive outer rd1 retina, we recorded spontaneous population activity in retinal wholemounts using Ca2+ imaging and identified the participating cell types. Focusing on cones, RBCs and horizontal cells (HCs, we found that these cell types display spontaneous oscillatory activity and form synchronously active clusters. Overall activity was modulated by GABAergic inhibition from HCs. Many of the activity clusters comprised both cones and RBCs. Opposite to what is expected from the intact (wild-type cone-ON bipolar cell pathway, cone and RBC activity was positively correlated and, at least partially, mediated by glutamate transporters expressed on RBCs. Deletion of gap junctional coupling between cones reduced the number of clusters, indicating that electrical cone coupling plays a crucial role for generating the observed synchronized oscillations. In conclusion, degeneration-induced synaptic remodeling of the rd1 retina results in a complex self-sustained outer retinal oscillatory network, that complements (and potentially modulates the recently described inner retinal oscillatory network consisting of amacrine, bipolar and ganglion cells.

  16. Ovariectomy does not exacerbate the negative effects of sleep deprivation on synaptic plasticity in rats.

    Science.gov (United States)

    Hajali, Vahid; Sheibani, Vahid; Mahani, Saeed E; Hajializadeh, Zahra; Shabani, Mohammad; Aliabadi, Hamzeh P; Saadati, Hakimeh; Esmaeilpour, Khadijeh

    2015-05-15

    In our previous work, we found that female rats showed more cognitive impairment than male rats following 72h sleep deprivation (SD). Here, we compared the intact female with ovariectomized (OVX) rats to assess the potential modulatory effects of endogenous female sex hormones against the 48h SD-induced cognitive and synaptic modulations. The multiple platform method was applied for SD induction and spatial performances were determined using Morris water maze (MWM) task. Early longterm potentiation (E-LTP) was evaluated in area CA1 of the hippocampus and PCR and western blotting assays were employed to assess hippocampal BDNF gene and protein expression. To reveal any influence of sleep loss on stress level, we also measured the plasma corticosterone levels of animals. Regardless of reproductive status, SD significantly impaired short-term memory and LTP, but did not significantly change the BDNF expression in the hippocampus. The corticosterone levels were decreased in both intact and OVX female rats following SD. These findings suggest that depletion of female sex steroid hormones does not lead to any heightened responsivity of female animals to the negative effects of SD on cognitive and synaptic functions. PMID:25748255

  17. Spike-Timing–Dependent Synaptic Plasticity and Synaptic Democracy in Dendrites

    Science.gov (United States)

    Gidon, Albert; Segev, Idan

    2009-01-01

    We explored in a computational study the effect of dendrites on excitatory synapses undergoing spike-timing–dependent plasticity (STDP), using both cylindrical dendritic models and reconstructed dendritic trees. We show that even if the initial strength, gpeak, of distal synapses is augmented in a location independent manner, the efficacy of distal synapses diminishes following STDP and proximal synapses would eventually dominate. Indeed, proximal synapses always win over distal synapses following linear STDP rule, independent of the initial synaptic strength distribution in the dendritic tree. This effect is more pronounced as the dendritic cable length increases but it does not depend on the dendritic branching structure. Adding a small multiplicative component to the linear STDP rule, whereby already strong synapses tend to be less potentiated than depressed (and vice versa for weak synapses) did partially “save” distal synapses from “dying out.” Another successful strategy for balancing the efficacy of distal and proximal synapses following STDP is to increase the upper bound for the synaptic conductance (gmax) with distance from the soma. We conclude by discussing an experiment for assessing which of these possible strategies might actually operate in dendrites. PMID:19357339

  18. Spike-timing-dependent synaptic plasticity and synaptic democracy in dendrites.

    Science.gov (United States)

    Gidon, Albert; Segev, Idan

    2009-06-01

    We explored in a computational study the effect of dendrites on excitatory synapses undergoing spike-timing-dependent plasticity (STDP), using both cylindrical dendritic models and reconstructed dendritic trees. We show that even if the initial strength, g(peak), of distal synapses is augmented in a location independent manner, the efficacy of distal synapses diminishes following STDP and proximal synapses would eventually dominate. Indeed, proximal synapses always win over distal synapses following linear STDP rule, independent of the initial synaptic strength distribution in the dendritic tree. This effect is more pronounced as the dendritic cable length increases but it does not depend on the dendritic branching structure. Adding a small multiplicative component to the linear STDP rule, whereby already strong synapses tend to be less potentiated than depressed (and vice versa for weak synapses) did partially "save" distal synapses from "dying out." Another successful strategy for balancing the efficacy of distal and proximal synapses following STDP is to increase the upper bound for the synaptic conductance (g(max)) with distance from the soma. We conclude by discussing an experiment for assessing which of these possible strategies might actually operate in dendrites.

  19. The origin of glutamatergic synaptic inputs controls synaptic plasticity and its modulation by alcohol in mice nucleus accumbens.

    Science.gov (United States)

    Ji, Xincai; Saha, Sucharita; Martin, Gilles E

    2015-01-01

    It is widely accepted that long-lasting changes of synaptic strength in the nucleus accumbens (NAc), a brain region involved in drug reward, mediate acute and chronic effects of alcohol. However, our understanding of the mechanisms underlying the effects of alcohol on synaptic plasticity is limited by the fact that the NAc receives glutamatergic inputs from distinct brain regions (e.g., the prefrontal cortex (PFCx), the amygdala and the hippocampus), each region providing different information (e.g., spatial, emotional and cognitive). Combining whole-cell patch-clamp recordings and the optogenetic technique, we examined synaptic plasticity, and its regulation by alcohol, at cortical, hippocampal and amygdala inputs in fresh slices of mouse tissue. We showed that the origin of synaptic inputs determines the basic properties of glutamatergic synaptic transmission, the expression of spike-timing dependent long-term depression (tLTD) and long-term potentiation (LTP) and long-term potentiation (tLTP) and their regulation by alcohol. While we observed both tLTP and tLTD at amygadala and hippocampal synapses, we showed that cortical inputs only undergo tLTD. Functionally, we provide evidence that acute Ethyl Alcohol (EtOH) has little effects on higher order information coming from the PFCx, while severely impacting the ability of emotional and contextual information to induce long-lasting changes of synaptic strength. PMID:26257641

  20. Ablation of Ca(V2.1 voltage-gated Ca²⁺ channels in mouse forebrain generates multiple cognitive impairments.

    Directory of Open Access Journals (Sweden)

    Robert Theodor Mallmann

    Full Text Available Voltage-gated Ca(V2.1 (P/Q-type Ca²⁺ channels located at the presynaptic membrane are known to control a multitude of Ca²⁺-dependent cellular processes such as neurotransmitter release and synaptic plasticity. Our knowledge about their contributions to complex cognitive functions, however, is restricted by the limited adequacy of existing transgenic Ca(V2.1 mouse models. Global Ca(V2.1 knock-out mice lacking the α1 subunit Cacna1a gene product exhibit early postnatal lethality which makes them unsuitable to analyse the relevance of Ca(V2.1 Ca²⁺ channels for complex behaviour in adult mice. Consequently we established a forebrain specific Ca(V2.1 knock-out model by crossing mice with a floxed Cacna1a gene with mice expressing Cre-recombinase under the control of the NEX promoter. This novel mouse model enabled us to investigate the contribution of Ca(V2.1 to complex cognitive functions, particularly learning and memory. Electrophysiological analysis allowed us to test the specificity of our conditional knock-out model and revealed an impaired synaptic transmission at hippocampal glutamatergic synapses. At the behavioural level, the forebrain-specific Ca(V2.1 knock-out resulted in deficits in spatial learning and reference memory, reduced recognition memory, increased exploratory behaviour and a strong attenuation of circadian rhythmicity. In summary, we present a novel conditional Ca(V2.1 knock-out model that is most suitable for analysing the in vivo functions of Ca(V2.1 in the adult murine forebrain.

  1. Usefulness of biphasic contrast injection in multidetector CT of the head and neck: A comparison with monophasic contrast injection

    International Nuclear Information System (INIS)

    The purpose of this study was to evaluate the value of biphasic injection of contrast media in a CT of the head and neck. In the first step, vessel and tissue attenuation was measured in four different protocol groups: M1 (monophasic, injection rate: 100 mL at 3 mL/sec, delay time: 70 sec); B1 (biphasic, 100 mL at 3 mL/sec, 70 sec); M2 (monophasic, 100 mL at 2 mL/sec, 70 sec); and B2 (biphasic, 100 mL at 2 mL/sec, 120 sec). The biphasic injection protocol was an initial volus injection of 50 mL contrast medium and an additional volus injection of 50 mL contrast medium at 35 sec after initial injection. In the second step, the tissue attenuation of two groups was measured with a different contrast media volume and phase: M3 (monophasic, 100 mL at 2 mL/sec, 90 sec) and B3 (biphasic, 80 mL at 2 mL/sec, 90 sec, initial volus injection of 40 mL and an additional volus injection of 40 mL at 55 sec after initial injection). The measured CT numbers from vessels and tissues were compared between the different protocol groups. The vessel attenuation of B1 was higher than that of M1 and B2 (p < 0.05). Despite a longer delay time, the vessel attenuation of B2 was not significantly different from that of M1 and M2. There was no significant differentiation of tissue attenuation between each group. In the second study, the attenuation of vessel and tissue was not different between B3 and M3. Biphasic contrast injection leads to an increased attenuation of the vessel and also delays the optimal scan window

  2. Mechanism-based pharmacokinetic-pharmacodynamic modeling of concentration-dependent hysteresis and biphasic electroencephalogram effects of alphaxalone in rats.

    Science.gov (United States)

    Visser, S A G; Smulders, C J G M; Reijers, B P R; Van der Graaf, P H; Peletier, L A; Danhof, M

    2002-09-01

    The neuroactive steroid alphaxalone reveals a complex biphasic concentration-effect relationship using the 11.5 to 30 Hz frequency band of the electroencephalogram (EEG) as biomarker. The purpose of the present investigation was to develop a mechanism-based pharmacokinetic-pharmacodynamic model to describe this observation. The proposed model is based on receptor theory and aims to separate the drug-receptor interaction from the transduction of the initial stimulus into the observed biphasic response. Individual concentration-time courses of alphaxalone were obtained in combination with continuous recording of the EEG parameter. Alphaxalone was administered intravenously in various dosages. The pharmacokinetics were described by a two-compartment model, and parameter estimates for clearance, intercompartmental clearance, volume of distribution 1 and 2 were 158 +/- 29 ml. min(-1). kg(-1), 143 +/- 31 ml. min(-1). kg(-1), 122 +/- 20 ml. kg(-1) and 606 +/- 48 ml. kg(-1), respectively. Concentration-effect relationships exhibited a biphasic pattern and delay in onset of effect. The hysteresis was described on the basis of an effect-compartment model with C(max) as covariate. The pharmacodynamic model consisted of a receptor model, featuring a monophasic saturable receptor activation model in combination with a biphasic stimulus-response model. The in vivo affinity (K(PD)) was estimated at 432 +/- 26 ng. ml(-1). Unique parameter estimates were obtained that were independent of the dose and the duration of the infusion. In conclusion, we have shown that this mechanism-based approach, which separates drug- and system-related properties in vivo, was successfully applied for the characterization of the biphasic effect versus time patterns of alphaxalone. The model should be of use in the characterization of other biphasic responses.

  3. Biphasic electrical currents stimulation promotes both proliferation and differentiation of fetal neural stem cells.

    Directory of Open Access Journals (Sweden)

    Keun-A Chang

    Full Text Available The use of non-chemical methods to differentiate stem cells has attracted researchers from multiple disciplines, including the engineering and the biomedical fields. No doubt, growth factor based methods are still the most dominant of achieving some level of proliferation and differentiation control--however, chemical based methods are still limited by the quality, source, and amount of the utilized reagents. Well-defined non-chemical methods to differentiate stem cells allow stem cell scientists to control stem cell biology by precisely administering the pre-defined parameters, whether they are structural cues, substrate stiffness, or in the form of current flow. We have developed a culture system that allows normal stem cell growth and the option of applying continuous and defined levels of electric current to alter the cell biology of growing cells. This biphasic current stimulator chip employing ITO electrodes generates both positive and negative currents in the same culture chamber without affecting surface chemistry. We found that biphasic electrical currents (BECs significantly increased the proliferation of fetal neural stem cells (NSCs. Furthermore, BECs also promoted the differentiation of fetal NSCs into neuronal cells, as assessed using immunocytochemistry. Our results clearly show that BECs promote both the proliferation and neuronal differentiation of fetal NSCs. It may apply to the development of strategies that employ NSCs in the treatment of various neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases.

  4. Online Epileptic Seizure Prediction Using Wavelet-Based Bi-Phase Correlation of Electrical Signals Tomography.

    Science.gov (United States)

    Vahabi, Zahra; Amirfattahi, Rasoul; Shayegh, Farzaneh; Ghassemi, Fahimeh

    2015-09-01

    Considerable efforts have been made in order to predict seizures. Among these methods, the ones that quantify synchronization between brain areas, are the most important methods. However, to date, a practically acceptable result has not been reported. In this paper, we use a synchronization measurement method that is derived according to the ability of bi-spectrum in determining the nonlinear properties of a system. In this method, first, temporal variation of the bi-spectrum of different channels of electro cardiography (ECoG) signals are obtained via an extended wavelet-based time-frequency analysis method; then, to compare different channels, the bi-phase correlation measure is introduced. Since, in this way, the temporal variation of the amount of nonlinear coupling between brain regions, which have not been considered yet, are taken into account, results are more reliable than the conventional phase-synchronization measures. It is shown that, for 21 patients of FSPEEG database, bi-phase correlation can discriminate the pre-ictal and ictal states, with very low false positive rates (FPRs) (average: 0.078/h) and high sensitivity (100%). However, the proposed seizure predictor still cannot significantly overcome the random predictor for all patients. PMID:26126613

  5. Differential Biphasic Transcriptional Host Response Associated with Coevolution of Hemagglutinin Quasispecies of Influenza A Virus

    Science.gov (United States)

    Manchanda, Himanshu; Seidel, Nora; Blaess, Markus F.; Claus, Ralf A.; Linde, Joerg; Slevogt, Hortense; Sauerbrei, Andreas; Guthke, Reinhard; Schmidtke, Michaela

    2016-01-01

    Severe influenza associated with strong symptoms and lung inflammation can be caused by intra-host evolution of quasispecies with aspartic acid or glycine in hemagglutinin position 222 (HA-222D/G; H1 numbering). To gain insights into the dynamics of host response to this coevolution and to identify key mechanisms contributing to copathogenesis, the lung transcriptional response of BALB/c mice infected with an A(H1N1)pdm09 isolate consisting HA-222D/G quasispecies was analyzed from days 1 to 12 post infection (p.i). At day 2 p.i. 968 differentially expressed genes (DEGs) were detected. The DEG number declined to 359 at day 4 and reached 1001 at day 7 p.i. prior to recovery. Interestingly, a biphasic expression profile was shown for the majority of these genes. Cytokine assays confirmed these results on protein level exemplarily for two key inflammatory cytokines, interferon gamma and interleukin 6. Using a reverse engineering strategy, a regulatory network was inferred to hypothetically explain the biphasic pattern for selected DEGs. Known regulatory interactions were extracted by Pathway Studio 9.0 and integrated during network inference. The hypothetic gene regulatory network revealed a positive feedback loop of Ifng, Stat1, and Tlr3 gene signaling that was triggered by the HA-G222 variant and correlated with a clinical symptom score indicating disease severity. PMID:27536272

  6. Aqueous biphasic extraction of uranium and thorium from contaminated soils. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Chaiko, D.J.; Gartelmann, J.; Henriksen, J.L.; Krause, T.R.; Deepak; Vojta, Y.; Thuillet, E.; Mertz, C.J.

    1995-07-01

    The aqueous biphasic extraction (ABE) process for soil decontamination involves the selective partitioning of solutes and fine particulates between two immiscible aqueous phases. The biphase system is generated by the appropriate combination of a water-soluble polymer (e.g., polyethlene glycol) with an inorganic salt (e.g., sodium carbonate). Selective partitioning results in 99 to 99.5% of the soil being recovered in the cleaned-soil fraction, while only 0.5 to 1% is recovered in the contaminant concentrate. The ABE process is best suited to the recovery of ultrafine, refractory material from the silt and clay fractions of soils. During continuous countercurrent extraction tests with soil samples from the Fernald Environmental Management Project site (Fernald, OH), particulate thorium was extracted and concentrated between 6- and 16-fold, while the uranium concentration was reduced from about 500 mg/kg to about 77 mg/kg. Carbonate leaching alone was able to reduce the uranium concentration only to 146 mg/kg. Preliminary estimates for treatment costs are approximately $160 per ton of dry soil. A detailed flowsheet of the ABE process is provided.

  7. Aqueous biphasic extraction of uranium and thorium from contaminated soils. Final report

    International Nuclear Information System (INIS)

    The aqueous biphasic extraction (ABE) process for soil decontamination involves the selective partitioning of solutes and fine particulates between two immiscible aqueous phases. The biphase system is generated by the appropriate combination of a water-soluble polymer (e.g., polyethlene glycol) with an inorganic salt (e.g., sodium carbonate). Selective partitioning results in 99 to 99.5% of the soil being recovered in the cleaned-soil fraction, while only 0.5 to 1% is recovered in the contaminant concentrate. The ABE process is best suited to the recovery of ultrafine, refractory material from the silt and clay fractions of soils. During continuous countercurrent extraction tests with soil samples from the Fernald Environmental Management Project site (Fernald, OH), particulate thorium was extracted and concentrated between 6- and 16-fold, while the uranium concentration was reduced from about 500 mg/kg to about 77 mg/kg. Carbonate leaching alone was able to reduce the uranium concentration only to 146 mg/kg. Preliminary estimates for treatment costs are approximately $160 per ton of dry soil. A detailed flowsheet of the ABE process is provided

  8. Superabsorbent biphasic system based on poly(lactic acid) and poly(acrylic acid)

    Science.gov (United States)

    Sartore, Luciana; Pandini, Stefano; Baldi, Francesco; Bignotti, Fabio

    2016-05-01

    In this research work, biocomposites based on crosslinked particles of poly(acrylic acid), commonly used as superabsorbent polymer (SAP), and poly-L-lactic acid (PLLA) were developed to elucidate the role of the filler (i.e., polymeric crosslinked particles) on the overall physico-mechanical behavior and to obtain superabsorbent thermoplastic products. Samples prepared by melt-blending of components in different ratios showed a biphasic system with a regular distribution of particles, with diameter ranging from 5 to 10 μm, within the PLLA polymeric matrix. The polymeric biphasic system, coded PLASA i.e. superabsorbent poly(lactic acid), showed excellent swelling properties, demonstrating that cross-linked particles retain their superabsorbent ability, as in their free counterparts, even if distributed in a thermoplastic polymeric matrix. The thermal characteristics of the biocomposites evidence enhanced thermal stability in comparison with neat PLLA and also mechanical properties are markedly modified by addition of crosslinked particles which induce regular stiffening effect. Furthermore, in aqueous environments the particles swell and are leached from PLLA matrix generating very high porosity. These new open-pore PLLA foams, produced in absence of organic solvents and chemical foaming agents, with good physico-mechanical properties appear very promising for several applications, for instance in tissue engineering for scaffold production.

  9. Efficient One-Pot Synthesis of 5-Chloromethylfurfural (CMF from Carbohydrates in Mild Biphasic Systems

    Directory of Open Access Journals (Sweden)

    Dimitris S. Argyropoulos

    2013-07-01

    Full Text Available 5-Halomethylfurfurals can be considered as platform chemicals of high reactivity making them useful for the preparation of a variety of important compounds. In this study, a one-pot route for the conversion of carbohydrates into 5-chloromethylfurfural (CMF in a simple and efficient (HCl-H3PO4/CHCl3 biphasic system has been investigated. Monosaccharides such as D-fructose, D-glucose and sorbose, disaccharides such as sucrose and cellobiose and polysaccharides such as cellulose were successfully converted into CMF in satisfactory yields under mild conditions. Our data shows that when using D-fructose the optimum yield of CMF was about 47%. This understanding allowed us to extent our work to biomaterials, such as wood powder and wood pulps with yields of CMF obtained being comparable to those seen with some of the enumerated mono and disaccharides. Overall, the proposed (HCl-H3PO4/CHCl3 optimized biphasic system provides a simple, mild, and cost-effective means to prepare CMF from renewable resources.

  10. Method for separating water soluble organics from a process stream by aqueous biphasic extraction

    Energy Technology Data Exchange (ETDEWEB)

    Chaiko, D.J.; Mego, W.A.

    1999-09-07

    A method for separating water-miscible organic species from a process stream by aqueous biphasic extraction is provided. An aqueous biphase system is generated by contacting a process stream comprised of water, salt, and organic species with an aqueous polymer solution. The organic species transfer from the salt-rich phase to the polymer-rich phase, and the phases are separated. Next, the polymer is recovered from the loaded polymer phase by selectively extracting the polymer into an organic phase at an elevated temperature, while the organic species remain in a substantially salt-free aqueous solution. Alternatively, the polymer is recovered from the loaded polymer by a temperature induced phase separation (cloud point extraction), whereby the polymer and the organic species separate into two distinct solutions. The method for separating water-miscible organic species is applicable to the treatment of industrial wastewater streams, including the extraction and recovery of complexed metal ions from salt solutions, organic contaminants from mineral processing streams, and colorants from spent dye baths.

  11. Method for separating water soluble organics from a process stream by aqueous biphasic extraction

    Energy Technology Data Exchange (ETDEWEB)

    Chaiko, David J. (Naperville, IL); Mego, William A. (Naperville, IL)

    1999-01-01

    A method for separating water-miscible organic species from a process stream by aqueous biphasic extraction is provided. An aqueous biphase system is generated by contacting a process stream comprised of water, salt, and organic species with an aqueous polymer solution. The organic species transfer from the salt-rich phase to the polymer-rich phase, and the phases are separated. Next, the polymer is recovered from the loaded polymer phase by selectively extracting the polymer into an organic phase at an elevated temperature, while the organic species remain in a substantially salt-free aqueous solution. Alternatively, the polymer is recovered from the loaded polymer by a temperature induced phase separation (cloud point extraction), whereby the polymer and the organic species separate into two distinct solutions. The method for separating water-miscible organic species is applicable to the treatment of industrial wastewater streams, including the extraction and recovery of complexed metal ions from salt solutions, organic contaminants from mineral processing streams, and colorants from spent dye baths.

  12. A New Explicit Algorithm for Bi-Phasic Mixture Flow in MIM

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    Metal injection moulding (MIM) is a new technology to manufacture small intricate parts in large quantity. Numerical simulation plays an important role in its development. To predict the specific segregation effect in MIM injection, mixture theory is adopted to model the injection flow by a bi-phasic model. This model conducts to the solution of two-coupled Stokes equations. It is an extremely computational consuming solution in the scope of the traditional algorithms, which induce a serious challenge to cost-effectivity of the MIM simulation. Referred to some methods proposed by Lewis in mono-phasic simulation and the implicit algorithms in MIM simulation, a new explicit algorithm is proposed and realized to perform efficiently this type of bi-phasic flow. Numerically this algorithm is devised to perform the simulation in a fully uncoupled manner except for a global solution of the pressure field in each time step. The physical coupling is taken into account in a sequential pattern by fractional steps. This special algorithm does not need any iteration, so it is straightforward and robust, suitable for MIM simulation and other sorts of simulations for multi-phasic flow.

  13. Charge-balanced biphasic electrical stimulation inhibits neurite extension of spiral ganglion neurons.

    Science.gov (United States)

    Shen, Na; Liang, Qiong; Liu, Yuehong; Lai, Bin; Li, Wen; Wang, Zhengmin; Li, Shufeng

    2016-06-15

    Intracochlear application of exogenous or transgenic neurotrophins, such as neurotrophin-3 (NT-3) and brain derived neurotrophic factor (BDNF), could promote the resprouting of spiral ganglion neuron (SGN) neurites in deafened animals. These resprouting neurites might reduce the gap between cochlear implant electrodes and their targeting SGNs, allowing for an improvement of spatial resolution of electrical stimulation. This study is to investigate the impact of electrical stimulation employed in CI on the extension of resprouting SGN neurites. We established an in vitro model including the devices delivering charge-balanced biphasic electrical stimulation, and spiral ganglion (SG) dissociated culture treated with BDNF and NT-3. After electrical stimulation with varying durations and intensities, we quantified neurite lengths and Schwann cell densities in SG cultures. Stimulations that were greater than 50μA or longer than 8h significantly decreased SG neurite length. Schwann cell density under 100μA electrical stimulation for 48h was significantly lower compared to that in non-stimulated group. These electrical stimulation-induced decreases of neurite extension and Schwann cell density were attenuated by various types of voltage-dependent calcium channel (VDCC) blockers, or completely prevented by their combination, cadmium or calcium-free medium. Our study suggested that charge-balanced biphasic electrical stimulation inhibited the extension of resprouting SGN neurites and decreased Schwann cell density in vitro. Calcium influx through multiple types of VDCCs was involved in the electrical stimulation-induced inhibition. PMID:27163199

  14. Biphasic pulses enhance bleomycin efficacy in a spontaneous canine genital tumor model of chemoresistance: Sticker sarcoma

    Directory of Open Access Journals (Sweden)

    Citro Gennaro

    2008-11-01

    Full Text Available Abstract Sticker's sarcoma (also known as transmissible venereal tumor is a horizontally transmitted neoplasm of the dog, that is passed with coitus. It is a locally aggressive tumor with a low tendency to metastatic spread. The most common locations are the genitals, the nose, the perianal area. Standard treatment consists with chemotherapy with vincristine, however other therapies such as, cryotherapy, immunotherapy or, in selected cases, radiation therapy, have been reported. In this article we describe the outcome of a small cohort of canine patients, with chemotherapy resistant transmissible venereal tumor (TVT, treated with bleomycin selectively driven by trains of biphasic pulses (electrochemotherapy. Three canine patients, with refractory TVT, entered the study and received two sessions of ECT under sedation. The pets had local injection of bleomycin at the concentration of 1.5 mg/ml and five minutes after the chemotherapy, trains of 8 biphasic electric pulses lasting 50 + 50 μs each, with 1 ms interpulse intervals, were delivered by means of modified caliper or, for difficult districts, through paired needle electrode. All the patients responded to the treatment and are still in remission at different times. Electrochemotherapy appears as a safe and efficacious modality for the treatment of TVT and warrants further investigations.

  15. Is there an Optimal Shape of the Defibrillation Shock: Constant Current vs. Pulsed Biphasic Waveforms

    Directory of Open Access Journals (Sweden)

    Ivan Dotsinsky

    2013-04-01

    Full Text Available Three waveforms for transthoracic defibrillation are assessed and compared: the Pulsed Biphasic Waveform (PBW, the Rectilinear Biphasic Waveform (RBW, and the "lossless" constant current (LLCC pulses. Two indices are introduced: 1 kf = W/W0 - the ratio between the delivered energy W and the energy W0 of a rectangular pulse with the same duration and electric charge; 2 ηC = W/WC0 - the level of utilizing the initially loaded capacitor energy WC0. The envisioned comparative study shows that ηC index is favorable for both PBW and LLCC, while kf of both RBW and LLCC demonstrates advantage over the PBW in the range of small inter-electrode thoracic impedances below 80 Ω. Some design considerations are also discussed. The attractive LLCC concept needs large and heavy inductive coil to support the constant current amplitude, besides it is capable to induce strong electromagnetic influences due to the complex current control. The RBW technology controls the delivery of current through a series of internal resistors which are, however, a source of high heat losses. The PBW implements controlled duty cycle of high-frequency chopped pulses to adapt the energy delivery in respect of the patient impedance measured at the beginning of the shock. PBW technology makes use of small capacitors which allows the construction of light weight and small-size portable devices for transthoracic defibrillation.

  16. On the appropriateness of modelling brain parenchyma as a biphasic continuum.

    Science.gov (United States)

    Tavner, A C R; Roy, T Dutta; Hor, K W W; Majimbi, M; Joldes, G R; Wittek, A; Bunt, S; Miller, K

    2016-08-01

    Computational methods originally developed for analysis in engineering have been applied to the analysis of biological materials for many years. One particular application of these engineering tools is the brain, allowing researchers to predict the behaviour of brain tissue in various traumatic, surgical and medical scenarios. Typically two different approaches have been used to model deformation of brain tissue: single-phase models which treat the brain as a viscoelastic material, and biphasic models which treat the brain as a porous deformable medium through which liquid can move. In order to model the brain as a biphasic continuum, the hydraulic conductivity of the solid phase is required; there are many theoretical values for this conductivity in the literature, with variations of up to three orders of magnitude. We carried out a series of simple experiments using lamb and sheep brain tissue to establish the rate at which cerebrospinal fluid moves through the brain parenchyma. Mindful of possible variations in hydraulic conductivity with tissue deformation, our intention was to carry out our experiments on brain tissue subjected to minimal deformation. This has enabled us to compare the rate of flow with values predicted by some of the theoretical values of hydraulic conductivity from the literature. Our results indicate that the hydraulic conductivity of the brain parenchyma is consistent with the lowest theoretical published values. These extremely low hydraulic conductivities lead to such low rates of CSF flow through the brain tissue that in effect the material behaves as a single-phase deformable solid. PMID:27136087

  17. Fabrication of nano structural biphasic materials from phosphogypsum waste and their in vitro applications

    Energy Technology Data Exchange (ETDEWEB)

    Mohamed, Khaled R., E-mail: Kh_rezk966@yahoo.com [Biomaterials Department, National Research Centre, Dokki, Cairo (Egypt); Mousa, Sahar M. [Chemistry Department, Science and Art College, King Abdulaziz University, Rabigh Campus, P.O. Box 344, 21911 Rabigh (Saudi Arabia); Inorganic Chemistry Department, National Research Centre, Dokki, P.O. Box 12622, 11787 Cairo (Egypt); El Bassyouni, Gehan T. [Biomaterials Department, National Research Centre, Dokki, Cairo (Egypt); Medical Physics Department, College of Medicine, Taif University (Saudi Arabia)

    2014-02-01

    Graphical abstract: (a) Schema of the process, (b) TEM of nano particles of biphasic materials and (c) SEM of post-immersion. - Highlights: • Ratio of HA and β-TCP phases were controlled by thermal treatment. • HA partially decomposed into β-TCP with other bioactive phases. • Calcined HA at 900 °C is the best for the bioactivity behavior. - Abstract: In this study, a novel process of preparing biphasic calcium phosphate (BCP) is proposed. Also its bioactivity for the utilization of the prepared BCP as a biomaterial is studied. A mixture of calcium hydroxyapatite (HAP) and tricalcium phosphate (β-TCP) could be obtained by thermal treatment of HAP which was previously prepared from phosphogypsum (PG) waste. The chemical and phase composition, morphology and particle size of prepared samples was characterized by X-ray diffraction (XRD), Infrared spectroscopy (IR), Scanning electron microscopy (SEM) and Transmission electron microscopy (TEM). The bioactivity was investigated by soaking of the calcined samples in simulated body fluid (SBF). Results confirmed that the calcination temperatures played an important role in the formation of calcium phosphate (CP) materials. XRD results indicated that HAP was partially decomposed into β-TCP. The in vitro data confirmed that the calcined HAP forming BCP besides other phases such as pyrophosphate and silica are bioactive materials. Therefore, BCP will be used as good biomaterials for medical applications.

  18. Biphasic products of dicalcium phosphate-rich cement with injectability and nondispersibility

    Energy Technology Data Exchange (ETDEWEB)

    Ko, Chia-Ling [Advanced Medical Devices and Composites Laboratory, Department of Fiber and Composite Materials, Feng Chia University, Taichung, 407, Taiwan (China); Dental Medical Devices and Materials Research Center, College of Dental Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan (China); Chen, Jian-Chih [Department of Orthopaedics, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan (China); Department of Orthopaedics, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan (China); Hung, Chun-Cheng; Wang, Jen-Chyan [Dental Medical Devices and Materials Research Center, College of Dental Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan (China); Department of Dentistry, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan (China); Tien, Yin-Chun [Department of Orthopaedics, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan (China); Department of Orthopaedics, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan (China); Chen, Wen-Cheng, E-mail: wencchen@fcu.edu.tw [Advanced Medical Devices and Composites Laboratory, Department of Fiber and Composite Materials, Feng Chia University, Taichung, 407, Taiwan (China)

    2014-06-01

    In this study, a calcium phosphate cement was developed using tetracalcium phosphate and surface-modified dicalcium phosphate anhydrous (DCPA). This developed injectable bone graft substitute can be molded to the shape of the bone cavity and set in situ through the piping system that has an adequate mechanical strength, non-dispersibility, and biocompatibility. The materials were based on the modified DCPA compositions of calcium phosphate cement (CPC), where the phase ratio of the surface-modified DCPA is higher than that of the conventional CPC for forming dicalcium phosphate (DCP)-rich cement. The composition and morphology of several calcium phosphate cement specimens during setting were analyzed via X-ray diffractometry and transmission electron microscopy coupled with an energy dispersive spectroscopy system. The compressive strength of DCP-rich CPCs was greater than 30 MPa after 24 h of immersion in vitro. The reaction of the CPCs produced steady final biphasic products of DCPs with apatite. The composites of calcium phosphate cements derived from tetracalcium phosphate mixed with surface-modified DCPA exhibited excellent mechanical properties, injectability, and interlocking forces between particles, and they also featured nondispersive behavior when immersed in a physiological solution. - Highlights: • Bone cement precursor with nanocrystals is characterized. • DCP-rich CPCs with nanocrystals exhibited biphasic product phases. • Nanocrystals in cement significantly affected the interlocking ability. • Nanocrystals in cement exhibited higher strength and anti-dispersion. • DCP-rich CPCs increase the potential of bioresorption after reaction.

  19. Influence of Biphasic Stimulation on Olfactory Ensheathing Cells for Neuroprosthetic Devices

    Science.gov (United States)

    Hassarati, Rachelle T.; Foster, L. John R.; Green, Rylie A.

    2016-01-01

    The recent success of olfactory ensheathing cell (OEC) assisted regeneration of injured spinal cord has seen a rising interest in the use of these cells in tissue-engineered systems. Previously shown to support neural cell growth through glial scar tissue, OECs have the potential to assist neural network formation in living electrode systems to produce superior neuroprosthetic electrode surfaces. The following study sought to understand the influence of biphasic electrical stimulation (ES), inherent to bionic devices, on cell survival and function, with respect to conventional metallic and developmental conductive hydrogel (CH) coated electrodes. The CH utilized in this study was a biosynthetic hydrogel consisting of methacrylated poly(vinyl-alcohol) (PVA), heparin and gelatin through which poly(3,4-ethylenedioxythiophene) (PEDOT) was electropolymerised. OECs cultured on Pt and CH surfaces were subjected to biphasic ES. Image-based cytometry yielded little significant difference between the viability and cell cycle of OECs cultured on the stimulated and passive samples. The significantly lower voltages measured across the CH electrodes (147 ± 3 mV) compared to the Pt (317 ± 5 mV), had shown to influence a higher percentage of viable cells on CH (91–93%) compared to Pt (78–81%). To determine the functionality of these cells following electrical stimulation, OECs co-cultured with PC12 cells were found to support neural cell differentiation (an indirect measure of neurotrophic factor production) following ES. PMID:27757072

  20. Biphasic dose-effect relationships in experimental studies of radiation cancer in animals

    International Nuclear Information System (INIS)

    Biphasic dose-effect relationships in radiation cancer are characterized by a decrease in cancer rate at low doses, a minimum and an increase at higher doses (inversion or radiation hormesis). A simple and argumentative methodology of proving such relationships is a model-free analysis which is based exclusively on the observed changes in cancer rate in dependence on dose without using special fitting functions. It is tested by means of well-known statistical tests whether the changes in cancer rate observed both in the low dose range and at higher doses are statistically significant. The model-free analysis of experimental results obtained in radiation cancer studies on RFM/Un-mice of both sexes and on female BC3F1-mice in the dose range 0.. 3 Gy by two independent research groups at Oak Ridge (ORNL) and at Casaccio near Rome leads for gamma radiation and X-rays to a statistically significant decrease of the cancer rate at low doses and therefore to biphasic relationships for tumors of the reticular tissue, for several solid tumors as well as for cancer as a whole. (orig.)

  1. Clinical experience of switching from biphasic human insulin to biphasic insulin aspart 30 in Indian patients with type 2 diabetes in the A 1 chieve study

    Directory of Open Access Journals (Sweden)

    A K Das

    2015-01-01

    Full Text Available Aim: The aim of the following study is to evaluate the safety and effectiveness of switching from biphasic human insulin (BHI to biphasic insulin aspart 30 (BIAsp 30 in Indian patients with type 2 diabetes as a sub-analysis of the 24-week, non-interventional A 1 chieve study. Materials and Methods: Indian patients switching from BHI to BIAsp 30 based on the physicians′ decisions were included. The primary outcome was the incidence of serious adverse drug reactions (SADRs, including major hypoglycemic events; secondary outcomes included changes in hypoglycemia in the 4 weeks preceding baseline and week 24 and changes from baseline to week 24 in glycated hemoglobin A 1c (HbA 1c , fasting plasma glucose (FPG, postprandial plasma glucose (PPPG, body weight and quality of life (QoL. Results: Overall, 1976 patients (mean ± standard deviation age, 55.1 ± 10.6 years and diabetes duration, 10.1 ± 5.3 years on a mean pre-study BHI dose of 0.44 ± 0.18 U/kg were included. The mean BIAsp 30 dose was 0.43 ± 0.17 U/kg at baseline and 0.44 ± 0.17 U/kg at week 24. No SADRs were reported. The proportion of patients reporting overall hypoglycemic events reduced significantly from baseline to week 24 (15.0% vs. 2.9%, P < 0.0001. The mean HbA 1c level improved significantly from 9.1 ± 1.4% at baseline to 7.5 ± 1.0% at week 24, along with improvements in FPG, post-breakfast PPPG and QoL (P < 0.001. The mean body weight decreased from 69.3 ± 10.8 kg at baseline to 69.1 ± 10.4 kg at week 24 (P = 0.003. Conclusion: Switching from BHI to BIAsp 30 therapy was well-tolerated and was associated with improved glycemic control.

  2. Concurrent imaging of synaptic vesicle recycling and calcium dynamics.

    Directory of Open Access Journals (Sweden)

    Haiyan eLi

    2011-11-01

    Full Text Available Synaptic transmission involves the calcium-dependent release of neurotransmitter from synaptic vesicles. Genetically encoded optical probes emitting different wavelengths of fluorescent light in response to neuronal activity offer a powerful approach to understand the spatial and temporal relationship of calcium dynamics to the release of neurotransmitter in defined neuronal populations. To simultaneously image synaptic vesicle recycling and changes in cytosolic calcium, we developed a red-shifted reporter of vesicle recycling based on a vesicular glutamate transporter, VGLUT1-mOrange2 (VGLUT1-mOr2, and a presynaptically-localized green calcium indicator, synaptophysin-GCaMP3 (SyGCaMP3 with a large dynamic range. The fluorescence of VGLUT1-mOr2 is quenched by the low pH of synaptic vesicles. Exocytosis upon electrical stimulation exposes the luminal mOr2 to the neutral extracellular pH and relieves fluorescence quenching. Re-acidification of the vesicle upon endocytosis again reduces fluorescence intensity. Changes in fluorescence intensity thus monitor synaptic vesicle exo- and endocytosis, as demonstrated previously for the green VGLUT1-pHluorin. To monitor changes in calcium, we fused the synaptic vesicle protein synaptophysin to the recently improved calcium indicator GCaMP3. SyGCaMP3 is targeted to presynaptic varicosities, and exhibits changes in fluorescence in response to electrical stimulation consistent with changes in calcium concentration. Using real-time imaging of both reporters expressed in the same synapses, we determine the time course of changes in VGLUT1 recycling in relation to changes in presynaptic calcium concentration. Inhibition of P/Q- and N-type calcium channels reduces calcium levels, as well as the rate of synaptic vesicle exocytosis and the fraction of vesicles released.

  3. Concurrent Imaging of Synaptic Vesicle Recycling and Calcium Dynamics

    Science.gov (United States)

    Li, Haiyan; Foss, Sarah M.; Dobryy, Yuriy L.; Park, C. Kevin; Hires, Samuel Andrew; Shaner, Nathan C.; Tsien, Roger Y.; Osborne, Leslie C.; Voglmaier, Susan M.

    2011-01-01

    Synaptic transmission involves the calcium dependent release of neurotransmitter from synaptic vesicles. Genetically encoded optical probes emitting different wavelengths of fluorescent light in response to neuronal activity offer a powerful approach to understand the spatial and temporal relationship of calcium dynamics to the release of neurotransmitter in defined neuronal populations. To simultaneously image synaptic vesicle recycling and changes in cytosolic calcium, we developed a red-shifted reporter of vesicle recycling based on a vesicular glutamate transporter, VGLUT1-mOrange2 (VGLUT1-mOr2), and a presynaptically localized green calcium indicator, synaptophysin-GCaMP3 (SyGCaMP3) with a large dynamic range. The fluorescence of VGLUT1-mOr2 is quenched by the low pH of synaptic vesicles. Exocytosis upon electrical stimulation exposes the luminal mOr2 to the neutral extracellular pH and relieves fluorescence quenching. Reacidification of the vesicle upon endocytosis again reduces fluorescence intensity. Changes in fluorescence intensity thus monitor synaptic vesicle exo- and endocytosis, as demonstrated previously for the green VGLUT1-pHluorin. To monitor changes in calcium, we fused the synaptic vesicle protein synaptophysin to the recently improved calcium indicator GCaMP3. SyGCaMP3 is targeted to presynaptic varicosities, and exhibits changes in fluorescence in response to electrical stimulation consistent with changes in calcium concentration. Using real time imaging of both reporters expressed in the same synapses, we determine the time course of changes in VGLUT1 recycling in relation to changes in presynaptic calcium concentration. Inhibition of P/Q- and N-type calcium channels reduces calcium levels, as well as the rate of synaptic vesicle exocytosis and the fraction of vesicles released. PMID:22065946

  4. Neuropeptide Y gene transfection inhibits post-epileptic hippocampal synaptic reconstruction

    Institute of Scientific and Technical Information of China (English)

    Fan Zhang; Wenqing Zhao; Wenling Li; Changzheng Dong; Xinying Zhang; Jiang Wu; Na Li; Chuandong Liang

    2013-01-01

    Exogenous neuropeptide Y has antiepileptic effects; however, the underlying mechanism and optimal administration method for neuropeptide Y are still unresolved. Previous studies have used intracerebroventricular injection of neuropeptide Y into animal models of epilepsy. In this study, a recombinant adeno-associated virus expression vector carrying the neuropeptide Y gene was injected into the lateral ventricle of rats, while the ipsilateral hippocampus was injected with kainic acid to establish the epileptic model. After transfection of neuropeptide Y gene, mossy fiber sprouting in the hippocampal CA3 region of epileptic rats was significantly suppressed, hippocampal synaptophysin (p38) mRNA and protein expression were inhibited, and epileptic seizures were reduced. These experimental findings indicate that a recombinant adeno-associated virus expression vector carrying the neuropeptide Y gene reduces mossy fiber sprouting and inhibits abnormal synaptophysin expression, thereby suppressing post-epileptic synaptic reconstruction.

  5. Cannabinoid CB1 receptor signaling dichotomously modulates inhibitory and excitatory synaptic transmission in rat inner retina.

    Science.gov (United States)

    Wang, Xiao-Han; Wu, Yi; Yang, Xiao-Fang; Miao, Yanying; Zhang, Chuan-Qiang; Dong, Ling-Dan; Yang, Xiong-Li; Wang, Zhongfeng

    2016-01-01

    In the inner retina, ganglion cells (RGCs) integrate and process excitatory signal from bipolar cells (BCs) and inhibitory signal from amacrine cells (ACs). Using multiple labeling immunohistochemistry, we first revealed the expression of the cannabinoid CB1 receptor (CB1R) at the terminals of ACs and BCs in rat retina. By patch-clamp techniques, we then showed how the activation of this receptor dichotomously regulated miniature inhibitory postsynaptic currents (mIPSCs), mediated by GABAA receptors and glycine receptors, and miniature excitatory postsynaptic currents (mEPSCs), mediated by AMPA receptors, of RGCs in rat retinal slices. WIN55212-2 (WIN), a CB1R agonist, reduced the mIPSC frequency due to an inhibition of L-type Ca(2+) channels no matter whether AMPA receptors were blocked. In contrast, WIN reduced the mEPSC frequency by suppressing T-type Ca(2+) channels only when inhibitory inputs to RGCs were present, which could be in part due to less T-type Ca(2+) channels of cone BCs, presynaptic to RGCs, being in an inactivation state under such condition. This unique feature of CB1R-mediated retrograde regulation provides a novel mechanism for modulating excitatory synaptic transmission in the inner retina. Moreover, depolarization of RGCs suppressed mIPSCs of these cells, an effect that was eliminated by the CB1R antagonist SR141716, suggesting that endocannabinoid is indeed released from RGCs.

  6. Ionotropic receptors at hippocampal mossy fibres: roles in axonal excitability, synaptic transmission and plasticity

    Directory of Open Access Journals (Sweden)

    Arnaud J Ruiz

    2013-01-01

    Full Text Available Dentate granule cells process information from the enthorinal cortex en route to the hippocampus proper. These neurons have a very negative resting membrane potential and are relatively silent in the slice preparation. They are also subject to strong feed-forward inhibition. Their unmyelinated axon or mossy fibre ramifies extensively in the hilus and projects to stratum lucidum where it makes giant en-passant boutons with CA3 pyramidal neurons. There is compelling evidence that mossy fibre boutons express presynaptic GABAA receptors, which are commonly found in granule cell dendrites. There is also suggestive evidence for the presence of other ionotropic receptors, including glycine, NMDA and kainate receptors, in mossy fibre boutons. These presynaptic receptors have been proposed to lead to mossy fibre membrane depolarisation. How this phenomenon alters the excitability of synaptic boutons, the shape of presynaptic action potentials, Ca2+ influx and neurotransmitter release has remained elusive, but high-resolution live imaging of individual varicosities and direct patch-clamp recordings have begun to shed light on these phenomena. Presynaptic GABAA and kainate receptors have also been reported to facilitate the induction of long-term potentiation at mossy fibre – CA3 synapses. Although mossy fibres are highly specialised, some of the principles emerging at this connection may apply elsewhere in the CNS.

  7. Stimulation of Synaptic Vesicle Exocytosis by the Mental Disease Gene DISC1 is Mediated by N-Type Voltage-Gated Calcium Channels.

    Science.gov (United States)

    Tang, Willcyn; Thevathasan, Jervis Vermal; Lin, Qingshu; Lim, Kim Buay; Kuroda, Keisuke; Kaibuchi, Kozo; Bilger, Marcel; Soong, Tuck Wah; Fivaz, Marc

    2016-01-01

    Lesions and mutations of the DISC1 (Disrupted-in-schizophrenia-1) gene have been linked to major depression, schizophrenia, bipolar disorder and autism, but the influence of DISC1 on synaptic transmission remains poorly understood. Using two independent genetic approaches-RNAi and a DISC1 KO mouse-we examined the impact of DISC1 on the synaptic vesicle (SV) cycle by population imaging of the synaptic tracer vGpH in hippocampal neurons. DISC1 loss-of-function resulted in a marked decrease in SV exocytic rates during neuronal stimulation and was associated with reduced Ca(2+) transients at nerve terminals. Impaired SV release was efficiently rescued by elevation of extracellular Ca(2+), hinting at a link between DISC1 and voltage-gated Ca(2+) channels. Accordingly, blockade of N-type Cav2.2 channels mimics and occludes the effect of DISC1 inactivation on SV exocytosis, and overexpression of DISC1 in a heterologous system increases Cav2.2 currents. Collectively, these results show that DISC1-dependent enhancement of SV exocytosis is mediated by Cav2.2 and point to aberrant glutamate release as a probable endophenotype of major psychiatric disorders. PMID:27378904

  8. Cannabinoid CB1 receptor calibrates excitatory synaptic balance in the mouse hippocampus.

    Science.gov (United States)

    Monory, Krisztina; Polack, Martin; Remus, Anita; Lutz, Beat; Korte, Martin

    2015-03-01

    The endocannabinoid system negatively regulates the release of various neurotransmitters in an activity-dependent manner, thereby influencing the excitability of neuronal circuits. In the hippocampus, cannabinoid type 1 (CB1) receptor is present on both GABAergic and glutamatergic axon terminals. CB1 receptor-deficient mice were previously shown to have increased hippocampal long-term potentiation (LTP). In this study, we have investigated the consequences of cell-type-specific deletion of the CB1 receptor on the induction of hippocampal LTP and on CA1 pyramidal cell morphology. Deletion of CB1 receptor in GABAergic neurons in GABA-CB1-KO mice leads to a significantly decreased hippocampal LTP compared with WT controls. Concomitantly, CA1 pyramidal neurons have a significantly reduced dendritic branching both on the apical and on the basal dendrites. Moreover, the average spine density on the apical dendrites of CA1 pyramidal neurons is significantly diminished. In contrast, in mice lacking CB1 receptor in glutamatergic cells (Glu-CB1-KO), hippocampal LTP is significantly enhanced and CA1 pyramidal neurons show an increased branching and an increased spine density in the apical dendritic region. Together, these results indicate that the CB1 receptor signaling system both on inhibitory and excitatory neurons controls functional and structural synaptic plasticity of pyramidal neurons in the hippocampal CA1 region to maintain an appropriate homeostatic state upon neuronal activation. Consequently, if the CB1 receptor is lost in either neuronal population, an allostatic shift will occur leading to a long-term dysregulation of neuronal functions.

  9. The neurotoxin 1-methyl-4-phenylpyridinium (MPP+ alters hippocampal excitatory synaptic transmission by modulation of the GABAergic system

    Directory of Open Access Journals (Sweden)

    YuYing eHuang

    2015-08-01

    Full Text Available The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP induces Parkinson’s disease (PD-like symptoms following administration to mice, monkeys and humans. A common view is that MPTP is metabolized to 1-methyl-4-phenylpyridinium ion (MPP+ to induce its neurodegenerative effects on dopaminergic neurons in the substantia nigra. Moreover, the hippocampus contains dopaminergic fibers, which are projecting from the ventral tegmental area, substantia nigra and pars compacta and contain the whole machinery required for dopamine synthesis making them sensitive to MPTP and MPP+. Here we present data showing that acute bath-application of MPP+ elicited a dose-dependent facilitation followed by a depression of synaptic transmission of hippocampal Schaffer collaterals-CA1 synapses in mice. The effects of MPP+ were not mediated by D1/D5- and D2-like receptor activation. Inhibition of the dopamine transporters (DAT did not prevent but increased the depression of excitatory postsynaptic field potentials. In the search for a possible mechanism, we observed that MPP+ reduced the appearance of polyspikes in population spikes recorded in str. pyramidale and increased the frequency of miniature inhibitory postsynaptic currents. The acute effect of MPP+ on synaptic transmission was attenuated by co-application of a GABAA receptor antagonist. Taking these data together, we suggest that MPP+ affects hippocampal synaptic transmission by enhancing some aspects of

  10. Acetyl-l-carnitine restores synaptic transmission and enhances the inducibility of stable LTP after oxygen-glucose deprivation.

    Science.gov (United States)

    Kocsis, Kitti; Frank, Rita; Szabó, József; Knapp, Levente; Kis, Zsolt; Farkas, Tamás; Vécsei, László; Toldi, József

    2016-09-22

    Hypoxic circumstances result in functional and structural impairments of the brain. Oxygen-glucose deprivation (OGD) on hippocampal slices is a technique widely used to investigate the consequences of ischemic stroke and the potential neuroprotective effects of different drugs. Acetyl-l-carnitine (ALC) is a naturally occurring substance in the body, and it can therefore be administered safely even in relatively high doses. In previous experiments, ALC pretreatment proved to be effective against global hypoperfusion. In the present study, we investigated whether ALC can be protective in an OGD model. We are not aware of any earlier study in which the long-term potentiation (LTP) function on hippocampal slices was measured after OGD. Therefore, we set out to determine whether an effective ALC concentration has an effect on synaptic plasticity after OGD in the hippocampal CA1 subfield of rats. A further aim was to investigate the mechanism underlying the protective effect of this compound. The experiments revealed that ALC is neuroprotective against OGD in a dose-dependent manner, which is manifested not only in the regeneration of the impaired synaptic transmission after the OGD, but also in the inducibility and stability of the LTP. In the case of the most effective concentration of ALC (500μM), use of a phosphoinositide 3-kinase (PI3K) inhibitor (LY294002) revealed that the PI3K/Akt signaling pathway has a key role in the restoration of the synaptic transmission and plasticity reached by ALC treatment. PMID:27378558

  11. In vivo effects of antibodies from patients with anti-NMDA receptor encephalitis: further evidence of synaptic glutamatergic dysfunction

    Directory of Open Access Journals (Sweden)

    Manto Mario

    2010-11-01

    Full Text Available Abstract Background A severe encephalitis that associates with auto-antibodies to the NR1 subunit of the NMDA receptor (NMDA-R was recently reported. Patients' antibodies cause a decrease of the density of NMDA-R and synaptic mediated currents, but the in vivo effects on the extracellular glutamate and glutamatergic transmission are unknown. Methods We investigated the acute metabolic effects of patients' CSF and purified IgG injected in vivo. Injections were performed in CA1 area of Ammon's horn and in premotor cortex in rats. Results Patient's CSF increased the concentrations of glutamate in the extracellular space. The increase was dose-dependent and was dramatic with purified IgG. Patients' CSF impaired both the NMDA- and the AMPA-mediated synaptic regulation of glutamate, and did not affect the glial transport of glutamate. Blockade of GABA-A receptors was associated with a marked elevation of extra-cellular levels of glutamate following a pretreatment with patients' CSF. Conclusion These results support a direct role of NMDA-R antibodies upon altering glutamatergic transmission. Furthermore, we provide additional evidence in vivo that NMDA-R antibodies deregulate the glutamatergic pathways and that the encephalitis associated with these antibodies is an auto-immune synaptic disorder.

  12. Synaptic transmission changes in fear memory circuits underlie key features of an animal model of schizophrenia.

    Science.gov (United States)

    Pollard, Marie; Varin, Christophe; Hrupka, Brian; Pemberton, Darrel J; Steckler, Thomas; Shaban, Hamdy

    2012-02-01

    Non-competitive antagonists of the N-methyl-d-aspartate receptor (NMDA) such as phencyclidine (PCP) elicit schizophrenia-like symptoms in healthy individuals. Similarly, PCP dosing in rats produces typical behavioral phenotypes that mimic human schizophrenia symptoms. Although schizophrenic behavioral phenotypes of the PCP model have been extensively studied, the underlying alterations of intrinsic neuronal properties and synaptic transmission in relevant limbic brain microcircuits remain elusive. Acute brain slice electrophysiology and immunostaining of inhibitory neurons were used to identify neuronal circuit alterations of the amygdala and hippocampus associated with changes in extinction of fear learning in rats following PCP treatment. Subchronic PCP application led to impaired long-term potentiation (LTP) and marked increases in the ratio of NMDA to 2-amino-3(5-methyl-3-oxo-1,2-oxazol-4-yl)propionic acid (AMPA) receptor-mediated currents at lateral amygdala (LA) principal neurons without alterations in parvalbumin (PV) as well as non-PV, glutamic acid decarboxylase 67 (GAD 67) immunopositive neurons. In addition, LTP was impaired at the Schaffer collateral to CA1 hippocampal pathway coincident with a reduction in colocalized PV and GAD67 immunopositive neurons in the CA3 hippocampal area. These effects occurred without changes in spontaneous events or intrinsic membrane properties of principal cells in the LA. The impairment of LTP at both amygdalar and hippocampal microcircuits, which play a key role in processing relevant survival information such as fear and extinction memory concurred with a disruption of extinction learning of fear conditioned responses. Our results show that subchronic PCP administration in rats impairs synaptic functioning in the amygdala and hippocampus as well as processing of fear-related memories. PMID:22085880

  13. Synaptic and non-synaptic mechanisms of amygdala recruitment into temporolimbic epileptiform activities.

    Science.gov (United States)

    Klueva, Julia; Munsch, Thomas; Albrecht, Doris; Pape, Hans-Christian

    2003-11-01

    Lateral amygdala (LA) activity during synchronized-epileptiform discharges in temporolimbic circuits was investigated in rat horizontal slices containing the amygdala, hippocampus (Hip), perirhinal (Prh) and lateral entorhinal (LEnt) cortex, through multiple-site extra- and intracellular recording techniques and measurement of the extracellular K+ concentration. Application of 4-aminopyridine (50 microm) induced epileptiform discharges in all regions under study. Slow interictal-like burst discharges persisted in the Prh/LEnt/LA after disconnection of the Hip, seemed to originate in the Prh as shown from time delay analyses, and often preceded the onset of ictal-like activity. Disconnection of the amygdala resulted in de-synchronization of epileptiform discharges in the LA from those in the Prh/LEnt. Interictal-like activity was intracellularly reflected in LA projection neurons as gamma-aminobutyric acid (GABA)A/B receptor-mediated synaptic responses, and depolarizing electrogenic events (spikelets) residing on the initial phase of the GABA response. Spikelets were considered antidromically conducted ectopic action potentials generated at axon terminals, as they were graded in amplitude, were not abolished through hyperpolarizing membrane responses (which effectively blocked evoked orthodromic action potentials), lacked a clear prepotential or synaptic potential, were not affected through blockers of gap junctions, and were blocked through remote application of tetrodotoxin at putative target areas of LA projection neurons. Remote application of a GABAB receptor antagonist facilitated spikelet generation. A transient elevation in the extracellular K+ level averaging 3 mm above baseline occurred in conjunction with interictal-like activity in all areas under study. We conclude that interictal-like discharges in the LA/LEnt/Prh spread in a predictable manner through the synaptic network with the Prh playing a leading role. The rise in extracellular K+ may provide a

  14. Cell-specific synaptic plasticity induced by network oscillations.

    Science.gov (United States)

    Zarnadze, Shota; Bäuerle, Peter; Santos-Torres, Julio; Böhm, Claudia; Schmitz, Dietmar; Geiger, Jörg Rp; Dugladze, Tamar; Gloveli, Tengis

    2016-01-01

    Gamma rhythms are known to contribute to the process of memory encoding. However, little is known about the underlying mechanisms at the molecular, cellular and network levels. Using local field potential recording in awake behaving mice and concomitant field potential and whole-cell recordings in slice preparations we found that gamma rhythms lead to activity-dependent modification of hippocampal networks, including alterations in sharp wave-ripple complexes. Network plasticity, expressed as long-lasting increases in sharp wave-associated synaptic currents, exhibits enhanced excitatory synaptic strength in pyramidal cells that is induced postsynaptically and depends on metabotropic glutamate receptor-5 activation. In sharp contrast, alteration of inhibitory synaptic strength is independent of postsynaptic activation and less pronounced. Further, we found a cell type-specific, directionally biased synaptic plasticity of two major types of GABAergic cells, parvalbumin- and cholecystokinin-expressing interneurons. Thus, we propose that gamma frequency oscillations represent a network state that introduces long-lasting synaptic plasticity in a cell-specific manner. PMID:27218453

  15. Synaptic membrane rafts: traffic lights for local neurotrophin signalling?

    Directory of Open Access Journals (Sweden)

    Barbara eZonta

    2013-10-01

    Full Text Available Lipid rafts, cholesterol and lipid rich microdomains, are believed to play important roles as platforms for the partitioning of transmembrane and synaptic proteins involved in synaptic signalling, plasticity and maintenance. There is increasing evidence of a physical interaction between post-synaptic densities and post-synaptic lipid rafts. Localization of proteins within lipid rafts is highly regulated, and therefore lipid rafts may function as traffic lights modulating and fine-tuning neuronal signalling. The tyrosine kinase neurotrophin receptors (Trk and the low-affinity p75 neurotrophin receptor (p75NTR are enriched in neuronal lipid rafts together with the intermediates of downstream signalling pathways, suggesting a possible role of rafts in neurotrophin signalling. Moreover, neurotrophins and their receptors are involved in the regulation of cholesterol metabolism. Cholesterol is an important component of lipid rafts and its depletion leads to gradual loss of synapses, underscoring the importance of lipid rafts for proper neuronal function. Here, we review and discuss the idea that translocation of neurotrophin receptors in synaptic rafts may account for the selectivity of their transduced signals.

  16. Reversible Recruitment of a Homeostatic Reserve Pool of Synaptic Vesicles Underlies Rapid Homeostatic Plasticity of Quantal Content.

    Science.gov (United States)

    Wang, Xueyong; Pinter, Martin J; Rich, Mark M

    2016-01-20

    Homeostatic regulation is essential for the maintenance of synaptic strength within the physiological range. The current study is the first to demonstrate that both induction and reversal of homeostatic upregulation of synaptic vesicle release can occur within seconds of blocking or unblocking acetylcholine receptors at the mouse neuromuscular junction. Our data suggest that the homeostatic upregulation of release is due to Ca(2+)-dependent increase in the size of the readily releasable pool (RRP). Blocking vesicle refilling prevented upregulation of quantal content (QC), while leaving baseline release relatively unaffected. This suggested that the upregulation of QC was due to mobilization of a distinct pool of vesicles that were rapidly recycled and thus were dependent on continued vesicle refilling. We term this pool the "homeostatic reserve pool." A detailed analysis of the time course of vesicle release triggered by a presynaptic action potential suggests that the homeostatic reserve pool of vesicles is normally released more slowly than other vesicles, but the rate of their release becomes similar to that of the major pool during homeostatic upregulation of QC. Remarkably, instead of finding a generalized increase in the recruitment of vesicles into RRP, we identified a distinct homeostatic reserve pool of vesicles that appear to only participate in synchronized release following homeostatic upregulation of QC. Once this small pool of vesicles is depleted by the block of vesicle refilling, homeostatic upregulation of QC is no longer observed. This is the first identification of the population of vesicles responsible for the blockade-induced upregulation of release previously described. Significance statement: The current study is the first to demonstrate that both the induction and reversal of homeostatic upregulation of synaptic vesicle release can occur within seconds. Our data suggest that homeostatic upregulation of release is due to Ca(2+)-dependent

  17. Impairment of cognitive function and synaptic plasticity associated with alteration of information flow in theta and gamma oscillations in melamine-treated rats.

    Directory of Open Access Journals (Sweden)

    Xiaxia Xu

    Full Text Available Changes of neural oscillations at a variety of physiological rhythms are effectively associated with cognitive performance. The present study investigated whether the directional indices of neural information flow (NIF could be used to symbolize the synaptic plasticity impairment in hippocampal CA3-CA1 network in a rat model of melamine. Male Wistar rats were employed while melamine was administered at a dose of 300 mg/kg/day for 4 weeks. Behavior was measured by the Morris water maze(MWMtest. Local field potentials (LFPs were recorded before long-term potentiation (LTP induction. Generalized partial directed coherence (gPDC and phase-amplitude coupling conditional mutual information (PAC_CMI were used to measure the unidirectional indices in both theta and low gamma oscillations (LG, ~ 30-50 Hz. Our results showed that melamine induced the cognition deficits consistent with the reduced LTP in CA1 area. Phase locking values (PLVs showed that the synchronization between CA3 and CA1 in both theta and LG rhythms was reduced by melamine. In both theta and LG rhythms, unidirectional indices were significantly decreased in melamine treated rats while a similar variation trend was observed in LTP reduction, implying that the effects of melamine on cognitive impairment were possibly mediated via profound alterations of NIF on CA3-CA1 pathway in hippocampus. The results suggested that LFPs activities at these rhythms were most likely involved in determining the alterations of information flow in the hippocampal CA3-CA1 network, which might be associated with the alteration of synaptic transmission to some extent.

  18. Calcium-sensing receptor activation depresses synaptic transmission

    OpenAIRE

    Phillips, Cecilia G.; Harnett, Mark T.; Chen, Wenyan; Smith, Stephen M.

    2008-01-01

    At excitatory synapses, decreases in cleft [Ca] arising from activity-dependent transmembrane Ca flux reduce the probability of subsequent transmitter release. Intense neural activity, induced by physiological and pathological stimuli, disturb the external microenvironment reducing extracellular [Ca] ([Ca]o) and thus may impair neurotransmission. Increases in [Ca]o activate the extracellular calcium sensing receptor (CaSR) which in turn inhibits non-selective cation channels (NSCC) at the maj...

  19. Storage capacity diverges with synaptic efficiency in an associative memory model with synaptic delay and pruning.

    Science.gov (United States)

    Miyoshi, Seiji; Okada, Masato

    2004-09-01

    It is known that storage capacity per synapse increases by synaptic pruning in the case of a correlation-type associative memory model. However, the storage capacity of the entire network then decreases. To overcome this difficulty, we propose decreasing the connectivity while keeping the total number of synapses constant by introducing delayed synapses. In this paper, a discrete synchronous-type model with both delayed synapses and their prunings is discussed as a concrete example of the proposal. First, we explain the Yanai-Kim theory by employing statistical neurodynamics. This theory involves macrodynamical equations for the dynamics of a network with serial delay elements. Next, considering the translational symmetry of the explained equations, we rederive macroscopic steady-state equations of the model by using the discrete Fourier transformation. The storage capacities are analyzed quantitatively. Furthermore, two types of synaptic prunings are treated analytically: random pruning and systematic pruning. As a result, it becomes clear that in both prunings, the storage capacity increases as the length of delay increases and the connectivity of the synapses decreases when the total number of synapses is constant. Moreover, an interesting fact becomes clear: the storage capacity asymptotically approaches 2/pi due to random pruning. In contrast, the storage capacity diverges in proportion to the logarithm of the length of delay by systematic pruning and the proportion constant is 4/pi. These results theoretically support the significance of pruning following an overgrowth of synapses in the brain and may suggest that the brain prefers to store dynamic attractors such as sequences and limit cycles rather than equilibrium states. PMID:15484896

  20. Biphasic calcium phosphate ceramic combined with fibrillar collagen with and without citric acid conditioning in the treatment of periodontal osseous defects.

    Science.gov (United States)

    Nery, E B; Eslami, A; Van Swol, R L

    1990-03-01

    The purpose of this study is to determine whether the combination of biphasic calcium phosphate ceramic (BCP) and collagen and citric acid root conditioning would promote accelerated new attachment of periodontal tissue to the root surface in dogs. Intrabony defects were surgically produced for each animal and were made chronic for 16 weeks. These defects were assigned to two study treatment and one control group: ceramic-collagen without citric acid (CO-CE); ceramic-collagen with citric acid (CO-CE-CA); and control (surgical debridement and root planing only). Results showed that all groups gained new attachment level as demonstrated both clinically and histometrically. The treatment groups showed a significant mean gain greater than the control (P less than .005), but no significant difference was found between treatment groups. Small areas of ankylosis was also found in both treatments but there was no evidence of active root resorption. It is concluded that the use of combined BCP and fibrillar collagen is beneficial in promoting new attachment of periodontal tissues to the root surface in dogs. Although citric acid root conditioning did as well or better than ceramic and collagen alone, its benefits are still speculative and need further experimentation.

  1. NH125 reduces the level of CPEB3, an RNA binding protein, to promote synaptic GluA2 expression.

    Science.gov (United States)

    Bender, Crhistian L; Yang, Qian; Sun, Lu; Liu, Siqiong June

    2016-02-01

    Neuronal activity can alter the phosphorylation state of eukaryotic elongation factor 2 (eEF2) and thereby regulates protein synthesis. This is thought to be the underlying mechanism for a form of synaptic plasticity that involves changes in the expression of synaptic AMPA type glutamate receptors. Phosphorylation of eEF2 by Ca/calmodulin-dependent eEF2 kinase reduces the activity of eEF2, and this is prevented by a commonly used eEF2 kinase inhibitor, NH125. Here we show that 10 μM NH125 increased the expression of synaptic GluA2-containing receptors in mouse cerebellar stellate cells and this was prevented by a protein synthesis inhibitor. However NH125 at 10 μM also reduced the level of CPEB3, a protein that is known to bind to GluA2 mRNA and suppress GluA2 (also known as GluR2) synthesis. In contrast, a low concentration of NH125 lowered the peEF2 level, but did not alter CPEB3 expression and also failed to increase synaptic GluA2 receptors. A selective eEF2 kinase inhibitor, A-484954, decreased the level of peEF2, without changing the expression of CPEB3. This suggests that reducing peEF2 does not lead to a decrease in CPEB3 levels and is not sufficient to increase GluA2 synthesis. Thus NH125 at 10 μM reduced the level of CPEB3, and promoted GluA2 translation via a mechanism independent of inhibition of eEF2 kinase. Therefore NH125 does not always alter protein synthesis via selective inhibition of eEF2 kinase and the effects of NH125 on translation of mRNAs should be interpreted with caution.

  2. Lead Exposure Impairs Hippocampus Related Learning and Memory by Altering Synaptic Plasticity and Morphology During Juvenile Period.

    Science.gov (United States)

    Wang, Tao; Guan, Rui-Li; Liu, Ming-Chao; Shen, Xue-Feng; Chen, Jing Yuan; Zhao, Ming-Gao; Luo, Wen-Jing

    2016-08-01

    Lead (Pb) is an environmental neurotoxic metal. Pb exposure may cause neurobehavioral changes, such as learning and memory impairment, and adolescence violence among children. Previous animal models have largely focused on the effects of Pb exposure during early development (from gestation to lactation period) on neurobehavior. In this study, we exposed Sprague-Dawley rats during the juvenile stage (from juvenile period to adult period). We investigated the synaptic function and structural changes and the relationship of these changes to neurobehavioral deficits in adult rats. Our results showed that juvenile Pb exposure caused fear-conditioned memory impairment and anxiety-like behavior, but locomotion and pain behavior were indistinguishable from the controls. Electrophysiological studies showed that long-term potentiation induction was affected in Pb-exposed rats, and this was probably due to excitatory synaptic transmission impairment in Pb-exposed rats. We found that NMDA and AMPA receptor-mediated current was inhibited, whereas the GABA synaptic transmission was normal in Pb-exposed rats. NR2A and phosphorylated GluR1 expression decreased. Moreover, morphological studies showed that density of dendritic spines declined by about 20 % in the Pb-treated group. The spine showed an immature form in Pb-exposed rats, as indicated by spine size measurements. However, the length and arborization of dendrites were unchanged. Our results suggested that juvenile Pb exposure in rats is associated with alterations in the glutamate receptor, which caused synaptic functional and morphological changes in hippocampal CA1 pyramidal neurons, thereby leading to behavioral changes. PMID:26141123

  3. Alterations in synaptic plasticity coincide with deficits in spatial working memory in presymptomatic 3xTg-AD mice.

    Science.gov (United States)

    Clark, Jason K; Furgerson, Matthew; Crystal, Jonathon D; Fechheimer, Marcus; Furukawa, Ruth; Wagner, John J

    2015-11-01

    Alzheimer's disease is a neurodegenerative condition believed to be initiated by production of amyloid-beta peptide, which leads to synaptic dysfunction and progressive memory loss. Using a mouse model of Alzheimer's disease (3xTg-AD), an 8-arm radial maze was employed to assess spatial working memory. Unexpectedly, the younger (3month old) 3xTg-AD mice were as impaired in the spatial working memory task as the older (8month old) 3xTg-AD mice when compared with age-matched NonTg control animals. Field potential recordings from the CA1 region of slices prepared from the ventral hippocampus were obtained to assess synaptic transmission and capability for synaptic plasticity. At 3months of age, the NMDA receptor-dependent component of LTP was reduced in 3xTg-AD mice. However, the magnitude of the non-NMDA receptor-dependent component of LTP was concomitantly increased, resulting in a similar amount of total LTP in 3xTg-AD and NonTg mice. At 8months of age, the NMDA receptor-dependent LTP was again reduced in 3xTg-AD mice, but now the non-NMDA receptor-dependent component was decreased as well, resulting in a significantly reduced total amount of LTP in 3xTg-AD compared with NonTg mice. Both 3 and 8month old 3xTg-AD mice exhibited reductions in paired-pulse facilitation and NMDA receptor-dependent LTP that coincided with the deficit in spatial working memory. The early presence of this cognitive impairment and the associated alterations in synaptic plasticity demonstrate that the onset of some behavioral and neurophysiological consequences can occur before the detectable presence of plaques and tangles in the 3xTg-AD mouse model of Alzheimer's disease.

  4. Maternal dietary loads of alpha-tocopherol increase synapse density and glial synaptic coverage in the hippocampus of adult offspring

    Directory of Open Access Journals (Sweden)

    S. Salucci

    2014-05-01

    Full Text Available An increased intake of the antioxidant α-Tocopherol (vitamin E is recommended in complicated pregnancies, to prevent free radical damage to mother and fetus. However, the anti-PKC and antimitotic activity of α-Tocopherol raises concerns about its potential effects on brain development. Recently, we found that maternal dietary loads of α-Tocopherol through pregnancy and lactation cause developmental deficit in hippocampal synaptic plasticity in rat offspring. The defect persisted into adulthood, with behavioral alterations in hippocampus-dependent learning. Here, using the same rat model of maternal supplementation, ultrastructural morphometric studies were carried out to provide mechanistic interpretation to such a functional impairment in adult offspring by the occurrence of long-term changes in density and morphological features of hippocampal synapses. Higher density of axo-spinous synapses was found in CA1 stratum radiatum of α-Tocopherol-exposed rats compared to controls, pointing to a reduced synapse pruning. No morphometric changes were found in synaptic ultrastructural features, i.e., perimeter of axon terminals, length of synaptic specializations, extension of bouton-spine contact. Glia-synapse anatomical relationship was also affected. Heavier astrocytic coverage of synapses was observed in Tocopherol-treated offspring, notably surrounding axon terminals; moreover, the percentage of synapses contacted by astrocytic endfeet at bouton-spine interface (tripartite synapses was increased. These findings indicate that gestational and neonatal exposure to supranutritional tocopherol intake can result in anatomical changes of offspring hippocampus that last through adulthood. These include a surplus of axo-spinous synapses and an aberrant glia-synapse relationship, which may represent the morphological signature of previously described alterations in synaptic plasticity and hippocampus-dependent learning.

  5. Bi-phasic titanium dioxide nanoparticles doped with nitrogen and neodymium for enhanced photocatalysis

    Science.gov (United States)

    Gomez, Virginia; Bear, Joseph C.; McNaughter, Paul D.; McGettrick, James D.; Watson, Trystan; Charbonneau, Cecile; O'Brien, Paul; Barron, Andrew R.; Dunnill, Charles W.

    2015-10-01

    Bi-phasic or multi-phasic composite nanoparticles for use in photocatalysis have been produced by a new synthetic approach. Sol-gel methods are used to deposit multiple layers of active material onto soluble substrates. In this work, a layer of rutile (TiO2) was deposited onto sodium chloride pellets followed by an annealing step and a layer of anatase. After dissolving the substrate, bi-phasic nanoparticles containing half anatase and half rutile TiO2; with ``Janus-like'' characteristics are obtained. Nitrogen and neodymium doping of the materials were observed to enhance the photocatalytic properties both under UV and white light irradiation. The unique advantage of this synthetic method is the ability to systematically dope separate sides of the nanoparticles. Nitrogen doping was found to be most effective on the anatase side of the nanoparticle while neodymium was found to be most effective on the rutile side. Rhodamine B dye was effectively photodegraded by co-doped particles under white light.Bi-phasic or multi-phasic composite nanoparticles for use in photocatalysis have been produced by a new synthetic approach. Sol-gel methods are used to deposit multiple layers of active material onto soluble substrates. In this work, a layer of rutile (TiO2) was deposited onto sodium chloride pellets followed by an annealing step and a layer of anatase. After dissolving the substrate, bi-phasic nanoparticles containing half anatase and half rutile TiO2; with ``Janus-like'' characteristics are obtained. Nitrogen and neodymium doping of the materials were observed to enhance the photocatalytic properties both under UV and white light irradiation. The unique advantage of this synthetic method is the ability to systematically dope separate sides of the nanoparticles. Nitrogen doping was found to be most effective on the anatase side of the nanoparticle while neodymium was found to be most effective on the rutile side. Rhodamine B dye was effectively photodegraded by co

  6. P-glycoprotein regulating biphasic insulin secretion in rat pancreatic beta cells

    Institute of Scientific and Technical Information of China (English)

    TANG Yun-zhao; LI Dai-qing; SUN Fu-jun; LI Li; YU De-min

    2009-01-01

    Background A 65-kD mdr1(multi-drug resistance protein 1,P-glycoprotein)-like protein has been suggested to be the regulatory protein to the chloride channel protein 3(CIC-3)mediating insulin granules acidification and release in mouse pancreatic beta cells.But the protein has not been deeply investigated.In this study,we identified existence of the 65-kda protein in rat islets and preliminarily explored its biological functions.Methods Total RNAs of rat kidneys served as positive controls,and pancreas,islets and INS-1 cells were extracted for reverse-transcript PCR(RT-PCR),respectively.The cDNAs were run with specific primers selected from the mRNA of abcblb encoding P-glycoprotein.All PCR products were visualized in agarose gel electrophoresis and sequenced.Homogenates of rat islets and INS-1 cells were applied to SDS-PAGE.P-glycoprotein was detected by a specific monoclonal antibody,C219.Biphasic insulin release was measured in static incubations of rat islets with radioimmunology assay.Results Compared with positive control,expression of the P-glycoprotein mRNA segments were detected in the islets,INS-1 cells and pancreas.Sequence analysis confirmed that the PCR products were matched with mRNA of P-glycoprotein.A 65-kda protein was recognized by the antibody in the islets homogenate but not in that of INS-1 cells in Western-blotting.Instead,the homogenate of INS-1 cells contained a 160-kda protein recognized by the antibody.Insulin secretion of rat islets were stimulated by high glucose(16.7mmol/L),and showed biphasic curve during 60-minute incubation.After co-incubation with cyclosporine A(CsA),specific inhibitor to P-glycoprotein,the second phase of insulin secretion was reduced significantly while the first phase was not influenced.Conclusions The 65-kda protein expressed in rat islets is most likely a mini-P-glycoprotein.It may play a key role regulating biphasic insulin release.

  7. Temperature dependence of microwave absorption phenomena in single and biphase soft magnetic microwires

    Energy Technology Data Exchange (ETDEWEB)

    El Kammouni, Rhimou, E-mail: elkammounirhimou@gmail.com [Instituto de Ciencia de Materiales de Madrid, CSIC, 28049 Madrid (Spain); Vázquez, Manuel [Instituto de Ciencia de Materiales de Madrid, CSIC, 28049 Madrid (Spain); Lezama, Luis [Depto. Química Inorgánica, Universidad País Vasco, UPV/EHU, Bilbao (Spain); Kurlyandskaya, Galina [Depto. Electricidad y Electrónica, Universidad País Vasco, UPV/EHU, Bilbao (Spain); Dept. Magnetism and Magnetic Nanomaterials, Ural Federal University, Ekaterinburg (Russian Federation); Kraus, Ludek [Institute of Physics, Academy of Sciences of the Czech Republic, Prague (Czech Republic)

    2014-11-15

    The microwave absorption phenomena of single and biphase magnetic microwires with soft magnetic behavior have been investigated as a function of DC applied magnetic field using two alternative techniques: (i) absorption measurements in the temperature range of 4–300 K using a spectrometer operating at X-band frequency, at 9.5 GHz, and (ii) room-temperature, RT, ferromagnetic resonance measurements in a network analyzer in the frequency range up to 20 GHz. Complementary low-frequency magnetic characterization was performed in a Vibrating Sample Magnetometer. Studies have been performed for 8 μm diameter small-magnetostriction amorphous CoFeSiB single-phase microwire, coated by micrometric Pyrex layer, and after electroplating an external shell, 2 µm or 4 µm thick, of FeNi alloys. For single phase CoFeSiB microwire, a single absorption is observed, whose DC field dependence of resonance frequency at RT fits to a Kittel-law behavior for in-plane magnetized thin film. The temperature dependence behavior shows a monotonic increase in the resonance field, H{sub r}, with temperature. A parallel reduction of the circular anisotropy field, H{sub K}, is deduced from the temperature dependence of hysteresis loops. For biphase, CoFeSiB/FeNi, microwires, the absorption phenomena at RT also follow the Kittel condition. The observed opposite evolution with temperature of resonance field, H{sub r}, in 2 and 4 µm thick FeNi samples is interpreted considering the opposite sign of magnetostriction of the respective FeNi layers. The stress-induced magnetic anisotropy field, H{sub K}, in the FeNi shell is deduced to change sign at around 130 K. - Highlights: • A single absorption phenomenon is observed for single phase CoFeSiB. • The T dependence of the microwave behavior shows a monotonic increase of H{sub r} with T. • The absorption at RT follows the Kittel condition for biphase CoFe/FeNi microwires. • The T dependence of resonant field of CoFe/FeNi is interpreted to be

  8. Plasmalemmal Na+/Ca2+ exchanger modulates Ca2+-dependent exocytotic release of glutamate from rat cortical astrocytes

    Directory of Open Access Journals (Sweden)

    Reno C Reyes

    2012-01-01

    Full Text Available Astroglial excitability operates through increases in Ca2+cyt (cytosolic Ca2+, which can lead to glutamatergic gliotransmission. In parallel fluctuations in astrocytic Na+cyt (cytosolic Na+ control metabolic neuronal-glial signalling, most notably through stimulation of lactate production, which on release from astrocytes can be taken up and utilized by nearby neurons, a process referred to as lactate shuttle. Both gliotransmission and lactate shuttle play a role in modulation of synaptic transmission and plasticity. Consequently, we studied the role of the PMCA (plasma membrane Ca2+-ATPase, NCX (plasma membrane Na+/Ca2+ exchanger and NKA (Na+/K+-ATPase in complex and coordinated regulation of Ca2+cyt and Na+cyt in astrocytes at rest and upon mechanical stimulation. Our data support the notion that NKA and PMCA are the major Na+ and Ca2+ extruders in resting astrocytes. Surprisingly, the blockade of NKA or PMCA appeared less important during times of Ca2+ and Na+ cytosolic loads caused by mechanical stimulation. Unexpectedly, NCX in reverse mode appeared as a major contributor to overall Ca2+ and Na+ homoeostasis in astrocytes both at rest and when these glial cells were mechanically stimulated. In addition, NCX facilitated mechanically induced Ca2+-dependent exocytotic release of glutamate from astrocytes. These findings help better understanding of astrocyte-neuron bidirectional signalling at the tripartite synapse and/or microvasculature. We propose that NCX operating in reverse mode could be involved in fast and spatially localized Ca2+-dependent gliotransmission, that would operate in parallel to a slower and more widely distributed gliotransmission pathway that requires metabotropically controlled Ca2+ release from the ER (endoplasmic reticulum.

  9. The effect of aging on synaptosomal Ca2+ transport in the brain.

    Science.gov (United States)

    Sun, A Y; Seaman, R N

    1977-03-01

    The effect of aging on Ca2+ -transport in synaptosomal preparations from rat brains was assessed by measuring the accumulation of radioactive 45Ca within these particles. Four groups of rats at 6, 12 24 and 30 months of age were used for this study. Synaptosomal particles were isolated from the cerebral cortex of each animal and the radioactive 45Ca inside the particles were measured after incubating the particles with media containing an energy source and 45Ca Cl2. Results indicated that the transport of 45Ca was lower in the younger rats than the older groups. A 20% increase was consistent with the old rats (30 mo) as compared with the young ones (6 mo). The increase in Ca2+ -transport across synaptic plasma membranes may be related to the transmitter release and behavioral activity after senescence. PMID:885150

  10. Reactive Oxygen Species: Physiological and Physiopathological Effects on Synaptic Plasticity.

    Science.gov (United States)

    Beckhauser, Thiago Fernando; Francis-Oliveira, José; De Pasquale, Roberto

    2016-01-01

    In the mammalian central nervous system, reactive oxygen species (ROS) generation is counterbalanced by antioxidant defenses. When large amounts of ROS accumulate, antioxidant mechanisms become overwhelmed and oxidative cellular stress may occur. Therefore, ROS are typically characterized as toxic molecules, oxidizing membrane lipids, changing the conformation of proteins, damaging nucleic acids, and causing deficits in synaptic plasticity. High ROS concentrations are associated with a decline in cognitive functions, as observed in some neurodegenerative disorders and age-dependent decay of neuroplasticity. Nevertheless, controlled ROS production provides the optimal redox state for the activation of transductional pathways involved in synaptic changes. Since ROS may regulate neuronal activity and elicit negative effects at the same time, the distinction between beneficial and deleterious consequences is unclear. In this regard, this review assesses current research and describes the main sources of ROS in neurons, specifying their involvement in synaptic plasticity and distinguishing between physiological and pathological processes implicated. PMID:27625575

  11. Synapses, synaptic activity and intraneuronal Aβ in Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Davide Tampellini

    2010-05-01

    Full Text Available β-amyloid peptide accumulation plays a central role in the pathogenesis of Alzheimer’s disease. Aberrant β-amyloid buildup in the brain has been shown to be present both in the extracellular space and within neurons. Synapses are important targets of β-amyloid, and alterations in synapses better correlate with cognitive impairment than amyloid plaques or neurofibrillary tangles. The link between β-amyloid and synapses became even tighter when it was discovered that β-amyloid accumulates within synapses and that synaptic activity modulates β-amyloid secretion. Currently, a central question in Alzheimer’s disease research is what role synaptic activity plays in the disease process, and how specifically β-amyloid is involved in the synaptic dysfunction that characterizes the disease.

  12. A dynamic model of interactions of Ca2+, calmodulin, and catalytic subunits of Ca2+/calmodulin-dependent protein kinase II.

    Directory of Open Access Journals (Sweden)

    Shirley Pepke

    2010-02-01

    Full Text Available During the acquisition of memories, influx of Ca2+ into the postsynaptic spine through the pores of activated N-methyl-D-aspartate-type glutamate receptors triggers processes that change the strength of excitatory synapses. The pattern of Ca2+influx during the first few seconds of activity is interpreted within the Ca2+-dependent signaling network such that synaptic strength is eventually either potentiated or depressed. Many of the critical signaling enzymes that control synaptic plasticity,including Ca2+/calmodulin-dependent protein kinase II (CaMKII, are regulated by calmodulin, a small protein that can bindup to 4 Ca2+ ions. As a first step toward clarifying how the Ca2+-signaling network decides between potentiation or depression, we have created a kinetic model of the interactions of Ca2+, calmodulin, and CaMKII that represents our best understanding of the dynamics of these interactions under conditions that resemble those in a postsynaptic spine. We constrained parameters of the model from data in the literature, or from our own measurements, and then predicted time courses of activation and autophosphorylation of CaMKII under a variety of conditions. Simulations showed that species of calmodulin with fewer than four bound Ca2+ play a significant role in activation of CaMKII in the physiological regime,supporting the notion that processing of Ca2+ signals in a spine involves competition among target enzymes for binding to unsaturated species of CaM in an environment in which the concentration of Ca2+ is fluctuating rapidly. Indeed, we showed that dependence of activation on the frequency of Ca2+ transients arises from the kinetics of interaction of fluctuating Ca2+with calmodulin/CaMKII complexes. We used parameter sensitivity analysis to identify which parameters will be most beneficial to measure more carefully to improve the accuracy of predictions. This model provides a quantitative base from which to build more complex dynamic

  13. Hierarchical Fabrication of Engineered Vascularized Bone Biphasic Constructs via Dual 3D Bioprinting: Integrating Regional Bioactive Factors into Architectural Design.

    Science.gov (United States)

    Cui, Haitao; Zhu, Wei; Nowicki, Margaret; Zhou, Xuan; Khademhosseini, Ali; Zhang, Lijie Grace

    2016-09-01

    A biphasic artificial vascularized bone construct with regional bioactive factors is presented using dual 3D bioprinting platform technique, thereby forming a large functional bone grafts with organized vascular networks. Biocompatible mussel-inspired chemistry and "thiol-ene" click reaction are used to regionally immobilize bioactive factors during construct fabrication for modulating or improving cellular events.

  14. The added predictive value of biphasic events in ST analysis of the fetal electrocardiogram for intrapartum fetal monitoring

    NARCIS (Netherlands)

    Becker, Jeroen H; Krikhaar, Anniek; Schuit, Ewoud; Mårtendal, Annika; Maršál, Karel; Kwee, Anneke; Visser, Gerard H A; Amer-Wåhlin, Isis

    2015-01-01

    OBJECTIVE: To study the predictive value of biphasic ST-events for interventions for suspected fetal distress and adverse neonatal outcome, when using ST-analysis of the fetal electrocardiogram (FECG) for intrapartum fetal monitoring. DESIGN: Prospective cohort study. SETTING: Three academic hospita

  15. Electrocatalytic oxidation of alcohols and diols in a biphasic medium using CeIV methanesulfonate as mediator

    International Nuclear Information System (INIS)

    Some alcohols and diols were oxidized electro-catalytically in a biphasic system using cerium methanesulphonate as mediator. A mixture of methanesulphonic acid solution and benzene was used and aldehydes, ketones and diacids were some of the principal products obtained with yield varying from 27 to 98%. In several cases selectivity was obtained. (author)

  16. Precise Synaptic Efficacy Alignment Suggests Potentiation Dominated Learning.

    Science.gov (United States)

    Hartmann, Christoph; Miner, Daniel C; Triesch, Jochen

    2015-01-01

    Recent evidence suggests that parallel synapses from the same axonal branch onto the same dendritic branch have almost identical strength. It has been proposed that this alignment is only possible through learning rules that integrate activity over long time spans. However, learning mechanisms such as spike-timing-dependent plasticity (STDP) are commonly assumed to be temporally local. Here, we propose that the combination of temporally local STDP and a multiplicative synaptic normalization mechanism is sufficient to explain the alignment of parallel synapses. To address this issue, we introduce three increasingly complex models: First, we model the idealized interaction of STDP and synaptic normalization in a single neuron as a simple stochastic process and derive analytically that the alignment effect can be described by a so-called Kesten process. From this we can derive that synaptic efficacy alignment requires potentiation-dominated learning regimes. We verify these conditions in a single-neuron model with independent spiking activities but more realistic synapses. As expected, we only observe synaptic efficacy alignment for long-term potentiation-biased STDP. Finally, we explore how well the findings transfer to recurrent neural networks where the learning mechanisms interact with the correlated activity of the network. We find that due to the self-reinforcing correlations in recurrent circuits under STDP, alignment occurs for both long-term potentiation- and depression-biased STDP, because the learning will be potentiation dominated in both cases due to the potentiating events induced by correlated activity. This is in line with recent results demonstrating a dominance of potentiation over depression during waking and normalization during sleep. This leads us to predict that individual spine pairs will be more similar after sleep compared to after sleep deprivation. In conclusion, we show that synaptic normalization in conjunction with coordinated

  17. Defective glycinergic synaptic transmission in zebrafish motility mutants

    Directory of Open Access Journals (Sweden)

    Hiromi Hirata

    2010-01-01

    Full Text Available Glycine is a major inhibitory neurotransmitter in the spinal cord and brainstem. Recently, in vivo analysis of glycinergic synaptic transmission has been pursued in zebrafish using molecular genetics. An ENU mutagenesis screen identified two behavioral mutants that are defective in glycinergic synaptic transmission. Zebrafish bandoneon (beo mutants have a defect in glrbb, one of the duplicated glycine receptor (GlyR β subunit genes. These mutants exhibit a loss of glycinergic synaptic transmission due to a lack of synaptic aggregation of GlyRs. Due to the consequent loss of reciprocal inhibition of motor circuits between the two sides of the spinal cord, motor neurons activate simultaneously on both sides resulting in bilateral contraction of axial muscles of beo mutants, eliciting the so-called ‘accordion’ phenotype. Similar defects in GlyR subunit genes have been observed in several mammals and are the basis for human hyperekplexia/startle disease. By contrast, zebrafish shocked (sho mutants have a defect in slc6a9, encoding GlyT1, a glycine transporter that is expressed by astroglial cells surrounding the glycinergic synapse in the hindbrain and spinal cord. GlyT1 mediates rapid uptake of glycine from the synaptic cleft, terminating synaptic transmission. In zebrafish sho mutants, there appears to be elevated extracellular glycine resulting in persistent inhibition of postsynaptic neurons and subsequent reduced motility, causing the ‘twitch once’ phenotype. We review current knowledge regarding zebrafish ‘accordion’ and ‘twitch once’ mutants, including beo and sho, and report the identification of a new α2 subunit that revises the phylogeny of zebrafish GlyRs.

  18. Emergence of Functional Specificity in Balanced Networks with Synaptic Plasticity.

    Directory of Open Access Journals (Sweden)

    Sadra Sadeh

    2015-06-01

    Full Text Available In rodent visual cortex, synaptic connections between orientation-selective neurons are unspecific at the time of eye opening, and become to some degree functionally specific only later during development. An explanation for this two-stage process was proposed in terms of Hebbian plasticity based on visual experience that would eventually enhance connections between neurons with similar response features. For this to work, however, two conditions must be satisfied: First, orientation selective neuronal responses must exist before specific recurrent synaptic connections can be established. Second, Hebbian learning must be compatible with the recurrent network dynamics contributing to orientation selectivity, and the resulting specific connectivity must remain stable for unspecific background activity. Previous studies have mainly focused on very simple models, where the receptive fields of neurons were essentially determined by feedforward mechanisms, and where the recurrent network was small, lacking the complex recurrent dynamics of large-scale networks of excitatory and inhibitory neurons. Here we studied the emergence of functionally specific connectivity in large-scale recurrent networks with synaptic plasticity. Our results show that balanced random networks, which already exhibit highly selective responses at eye opening, can develop feature-specific connectivity if appropriate rules of synaptic plasticity are invoked within and between excitatory and inhibitory populations. If these conditions are met, the initial orientation selectivity guides the process of Hebbian learning and, as a result, functionally specific and a surplus of bidirectional connections emerge. Our results thus demonstrate the cooperation of synaptic plasticity and recurrent dynamics in large-scale functional networks with realistic receptive fields, highlight the role of inhibition as a critical element in this process, and paves the road for further computational

  19. Precise synaptic efficacy alignment suggests potentiation dominated learning

    Directory of Open Access Journals (Sweden)

    Christoph eHartmann

    2016-01-01

    Full Text Available Recent evidence suggests that parallel synapses from the same axonal branch onto the same dendritic branch have almost identical strength. It has been proposed that this alignment is only possible through learning rules that integrate activity over long time spans. However, learning mechanisms such as spike-timing-dependent plasticity (STDP are commonly assumed to be temporally local. Here, we propose that the combination of temporally local STDP and a multiplicative synaptic normalization mechanism is sufficient to explain the alignment of parallel synapses.To address this issue, we introduce three increasingly complex models: First, we model the idealized interaction of STDP and synaptic normalization in a single neuron as a simple stochastic process and derive analytically that the alignment effect can be described by a so-called Kesten process. From this we can derive that synaptic efficacy alignment requires potentiation-dominated learning regimes. We verify these conditions in a single-neuron model with independent spiking activities but more realistic synapses. As expected, we only observe synaptic efficacy alignment for long-term potentiation-biased STDP. Finally, we explore how well the findings transfer to recurrent neural networks where the learning mechanisms interact with the correlated activity of the network. We find that due to the self-reinforcing correlations in recurrent circuits under STDP, alignment occurs for both long-term potentiation- and depression-biased STDP, because the learning will be potentiation dominated in both cases due to the potentiating events induced by correlated activity. This is in line with recent results demonstrating a dominance of potentiation over depression during waking and normalization during sleep. This leads us to predict that individual spine pairs will be more similar in the morning than they are after sleep depriviation.In conclusion, we show that synaptic normalization in conjunction with

  20. A trans-synaptic nanocolumn aligns neurotransmitter release to receptors.

    Science.gov (United States)

    Tang, Ai-Hui; Chen, Haiwen; Li, Tuo P; Metzbower, Sarah R; MacGillavry, Harold D; Blanpied, Thomas A

    2016-08-11

    Synaptic transmission is maintained by a delicate, sub-synaptic molecular architecture, and even mild alterations in synapse structure drive functional changes during experience-dependent plasticity and pathological disorders. Key to this architecture is how the distribution of presynaptic vesicle fusion sites corresponds to the position of receptors in the postsynaptic density. However, while it has long been recognized that this spatial relationship modulates synaptic strength, it has not been precisely described, owing in part to the limited resolution of light microscopy. Using localization microscopy, here we show that key proteins mediating vesicle priming and fusion are mutually co-enriched within nanometre-scale subregions of the presynaptic active zone. Through development of a new method to map vesicle fusion positions within single synapses in cultured rat hippocampal neurons, we find that action-potential-evoked fusion is guided by this protein gradient and occurs preferentially in confined areas with higher local density of Rab3-interacting molecule (RIM) within the active zones. These presynaptic RIM nanoclusters closely align with concentrated postsynaptic receptors and scaffolding proteins, suggesting the existence of a trans-synaptic molecular 'nanocolumn'. Thus, we propose that the nanoarchitecture of the active zone directs action-potential-evoked vesicle fusion to occur preferentially at sites directly opposing postsynaptic receptor-scaffold ensembles. Remarkably, NMDA receptor activation triggered distinct phases of plasticity in which postsynaptic reorganization was followed by trans-synaptic nanoscale realignment. This architecture suggests a simple organizational principle of central nervous system synapses to maintain and modulate synaptic efficiency. PMID:27462810

  1. Depression as a Glial-Based Synaptic Dysfunction

    Directory of Open Access Journals (Sweden)

    Daniel eRial

    2016-01-01

    Full Text Available Recent studies combining pharmacological, behavioral, electrophysiological and molecular approaches indicate that depression results from maladaptive neuroplastic processing occurring in defined frontolimbic circuits responsible for emotional processing such as the prefrontal cortex, hippocampus, amygdala and ventral striatum. However, the exact mechanisms controlling synaptic plasticity that are disrupted to trigger depressive conditions have not been elucidated. Since glial cells (astrocytes and microglia tightly and dynamically interact with synapses, engaging a bi-directional communication critical for the processing of synaptic information, we now revisit the role of glial cells in the etiology of depression focusing on a dysfunction of the ‘quad-partite’ synapse. This interest is supported by the observations that depressive-like conditions are associated with a decreased density and hypofunction of astrocytes and with an increase microglia ‘activation’ in frontolimbic regions, which is expected to contribute for the synaptic dysfunction present in depression. Furthermore, the traditional culprits of depression (glucocorticoids, biogenic amines, BDNF affect glia functioning, whereas antidepressant treatments (SSRIs, electroshock, deep brain stimulation recover glia functioning. In this context of a quad-partite synapse, systems modulating glia-synapse bidirectional communication - such as the purinergic neuromodulation system operated by ATP and adenosine - emerge as promising candidates to re-normalize synaptic function by combining direct synaptic effects with an ability to also control astrocyte and microglia function. This proposed triple action of purines to control aberrant synaptic function illustrates the rationale to consider the interference with glia dysfunction as a mechanism of action driving the design of future pharmacological tools to manage depression.

  2. Inhibition of hippocampal synaptic transmission by impairment of Ral function

    DEFF Research Database (Denmark)

    Owe-Larsson, Björn; Chaves-Olarte, Esteban; Chauhan, Ashok;

    2005-01-01

    Large clostridial cytotoxins and protein overexpression were used to probe for involvement of Ras-related GTPases (guanosine triphosphate) in synaptic transmission in cultured rat hippocampal neurons. The toxins TcdA-10463 (inactivates Rho, Rac, Cdc42, Rap) and TcsL-1522 (inactivates Ral, Rac, Ras......, R-Ras, Rap) both inhibited autaptic responses. In a proportion of the neurons (25%, TcdA-10463; 54%, TcsL-1522), the inhibition was associated with a shift from activity-dependent depression to facilitation, indicating that the synaptic release probability was reduced. Overexpression of a dominant...

  3. Synaptic model for spontaneous activity in developing networks

    DEFF Research Database (Denmark)

    Lerchner, Alexander; Rinzel, J.

    2005-01-01

    Spontaneous rhythmic activity occurs in many developing neural networks. The activity in these hyperexcitable networks is comprised of recurring "episodes" consisting of "cycles" of high activity that alternate with "silent phases" with little or no activity. We introduce a new model of synaptic...... dynamics that takes into account that only a fraction of the vesicles stored in a synaptic terminal is readily available for release. We show that our model can reproduce spontaneous rhythmic activity with the same general features as observed in experiments, including a positive correlation between...

  4. Detection of spontaneous synaptic events with an optimally scaled template.

    OpenAIRE

    Clements, J. D.; Bekkers, J M

    1997-01-01

    Spontaneous synaptic events can be difficult to detect when their amplitudes are close to the background noise level. Here we report a sensitive new technique for automatic detection of small asynchronous events. A waveform with the time course of a typical synaptic event (a template) is slid along the current or voltage trace and optimally scaled to fit the data at each position. A detection criterion is calculated based on the optimum scaling factor and the quality of the fit. An event is d...

  5. A memristor SPICE model accounting for synaptic activity dependence.

    Directory of Open Access Journals (Sweden)

    Qingjiang Li

    Full Text Available In this work, we propose a new memristor SPICE model that accounts for the typical synaptic characteristics that have been previously demonstrated with practical memristive devices. We show that this model could account for both volatile and non-volatile memristance changes under distinct stimuli. We then demonstrate that our model is capable of supporting typical STDP with simple non-overlapping digital pulse pairs. Finally, we investigate the capability of our model to simulate the activity dependence dynamics of synaptic modification and present simulated results that are in excellent agreement with biological results.

  6. Autonomous CaMKII Mediates Both LTP and LTD Using a Mechanism for Differential Substrate Site Selection

    Directory of Open Access Journals (Sweden)

    Steven J. Coultrap

    2014-02-01

    Full Text Available Traditionally, hippocampal long-term potentiation (LTP of synaptic strength requires Ca2+/calmodulin (CaM-dependent protein kinase II (CaMKII and other kinases, whereas long-term depression (LTD requires phosphatases. Here, we found that LTD also requires CaMKII and its phospho-T286-induced “autonomous” (Ca2+-independent activity. However, whereas LTP is known to induce phosphorylation of the AMPA-type glutamate receptor (AMPAR subunit GluA1 at S831, LTD instead induced CaMKII-mediated phosphorylation at S567, a site known to reduce synaptic GluA1 localization. GluA1 S831 phosphorylation by “autonomous” CaMKII was further stimulated by Ca2+/CaM, as expected for traditional substrates. By contrast, GluA1 S567 represents a distinct substrate class that is unaffected by such stimulation. This differential regulation caused GluA1 S831 to be favored by LTP-type stimuli (strong but brief, whereas GluA1 S567 was favored by LTD-type stimuli (weak but prolonged. Thus, requirement of autonomous CaMKII in opposing forms of plasticity involves distinct substrate classes that are differentially regulated to enable stimulus-dependent substrate-site preference.

  7. Experimental study on bi-phase flow Air-Oil in Water Emulsion

    Science.gov (United States)

    Arnone, Davide; Poesio, Pietro

    2015-11-01

    Bi-phase slug flow oil-in-water emulsion [5%-20%] and air through a horizontal pipe (inner diameter 22mm) is experimentally studied. A test with water and air has been performed as comparison. First we create and analyze the flow pattern map to identify slug flow liquid and air inlet conditions. Flow maps are similar for all the used liquid. A video analysis procedure using an high speed camera has been created to obtain all the characteristics of unit slugs: slug velocity, slug length, bubble velocity, bubbles length and slug frequency. We compare translational velocity and frequency with models finding a good agreement. We calculate the pdfs of the lengths to find the correlations between mean values and STD on different air and liquid superficial velocities. We also perform pressure measurements along the pipe. We conclude that the percentage of oil-in- water has no influence on results in terms of velocity, lengths, frequency and pressure drop.

  8. A biphasic oxidation of alcohols to aldehydes and ketones using a simplified packed-bed microreactor

    Directory of Open Access Journals (Sweden)

    Andrew Bogdan

    2009-04-01

    Full Text Available We demonstrate the preparation and characterization of a simplified packed-bed microreactor using an immobilized TEMPO catalyst shown to oxidize primary and secondary alcohols via the biphasic Anelli-Montanari protocol. Oxidations occurred in high yields with great stability over time. We observed that plugs of aqueous oxidant and organic alcohol entered the reactor as plugs but merged into an emulsion on the packed-bed. The emulsion coalesced into larger plugs upon exiting the reactor, leaving the organic product separate from the aqueous by-products. Furthermore, the microreactor oxidized a wide range of alcohols and remained active in excess of 100 trials without showing any loss of catalytic activity.

  9. Kinetics of protein-protein complex coacervation and biphasic release of salbutamol sulfate from coacervate matrix.

    Science.gov (United States)

    Tiwari, Ananya; Bindal, Sonal; Bohidar, H B

    2009-01-12

    Turbidimetric titration was used to initiate associative intermolecular interactions between a pair of protein molecules, gelatin-A and gelatin-B, having complementary charges that led to pH-induced liquid-liquid phase separation and the formation of complex coacervate. The stoichiometric binding ratio was found to be [gelatin-A]/[gelatin-B]=3:2. The size of soluble intermolecular aggregates present in the supernatant exhibited interesting time-dependent coacervation because of residual electrostatic interactions. Dynamic light scattering and turbidity studies provided a systematic account of coacervation behavior. Rheology studies attributed the softening of the coacervate matrix to the presence of encapsulated salbutamol sulfate. The in vitro drug release kinetics was probed in simulated gastric fluid medium at physiological temperature (37 degrees C), which showed biphasic behavior. The initial release kinetics exhibited an exponential growth to saturation behavior, followed by a slower logarithmic release process.

  10. Injectable Hydrogel Composite Based Gelatin-PEG and Biphasic Calcium Phosphate Nanoparticles for Bone Regeneration

    Science.gov (United States)

    Van, Thuy Duong; Tran, Ngoc Quyen; Nguyen, Dai Hai; Nguyen, Cuu Khoa; Tran, Dai Lam; Nguyen, Phuong Thi

    2016-05-01

    Gelatin hydrogels have recently attracted much attention for tissue regeneration because of their biocompatibility. In this study, we introduce poly-ethylene glycol (PEG)—grafted gelatin containing tyramine moieties which have been utilized for in situ enzyme-mediated hydrogel preparation. The hydrogel can be used to load nanoparticles of biphasic calcium phosphate, a mixture of hydroxyapatite and β-tricalcium phosphate, and forming injectable bio-composites. Proton nuclear magnetic resonance (1H NMR) spectra indicated that tyramine-functionalized polyethylene glycol-nitrophenyl carbonate ester was conjugated to the gelatin. The hydrogel composite was rapidly formed in situ (within a few seconds) in the presence of horseradish peroxidase and hydrogen peroxide. In vitro experiments with bio-mineralization on the hydrogel composite surfaces was well-observed after 2 weeks soaking in simulated body fluid solution. The obtained results indicated that the hydrogel composite could be a potential injectable material for bone regeneration.

  11. A new biphasic osteoinductive calcium composite material with a negative Zeta potential for bone augmentation

    Directory of Open Access Journals (Sweden)

    Maciejewski Oliver

    2009-06-01

    Full Text Available Abstract The aim of the present study was to analyze the osteogenic potential of a biphasic calcium composite material (BCC with a negative surface charge for maxillary sinus floor augmentation. In a 61 year old patient, the BCC material was used in a bilateral sinus floor augmentation procedure. Six months postoperative, a bone sample was taken from the augmented regions before two titanium implants were inserted at each side. We analyzed bone neoformation by histology, bone density by computed tomography, and measured the activity of voltage-activated calcium currents of osteoblasts and surface charge effects. Control orthopantomograms were carried out five months after implant insertion. The BCC was biocompatible and replaced by new mineralized bone after being resorbed completely. The material demonstrated a negative surface charge (negative Zeta potential which was found to be favorable for bone regeneration and osseointegration of dental implants.

  12. [Biphasic mesothelioma in a Swiss Braunvieh cow: clinical, histological, immunohistochemical and electron microscopical findings].

    Science.gov (United States)

    Braun, Ueli; Rütten, M; Bleul, U; Previtali, M; Krüger, S; Gerspach, C; Geiger, S; Sydler, T

    2012-01-01

    A 10-year-old Swiss Braunvieh cow near term was referred to our clinic because of severe abdominal distension, which caused loss of demarcation between the udder and ventral abdominal wall. Ultrasonographic examination revealed marked ascites and multiple echogenic nodules in the greater omentum. Based on the findings, non-inflammatory ascites attributable to neoplasia was diagnosed. Rupture of the prepubic tendon from the pubic symphysis was also suspected. Because of a grave prognosis, parturition was induced and a live calf was delivered. The cow was euthanized and a postmortem examination was carried out. The abdominal cavity contained 248.5 litres of clear fluid. The greater omentum was thickened and oedematous and regionally contained fluid-filled cystic structures, which varied in size with a maximum diameter of 10 centimetres. Based on the histological, immunohistochemical and electron microscopical findings, biphasic mesothelioma with cyst formation affecting the entire abdominal cavity was diagnosed.

  13. Obtaining of ceramics biphasic dense and porous; Obtencao de ceramicas bifasicas densas e porosas

    Energy Technology Data Exchange (ETDEWEB)

    Pallone, E.M.J.A.; Rigo, E.C.S., E-mail: eliria@usp.b [Universidade de Sao Paulo (FZEA/USP), Pirassununga, SP (Brazil). Dept. de Ciencias Basicas; Silva, K.L. [Universidade Estadual de Campinas (FEM/UNICAMP), SP (Brazil). Faculdade de Engenharia Mecanica; Rezende, M.E. [Universidade Sao Francisco, Itatiba, SP (Brazil); Fraga, A.F. [Universidade Federal de Sao Carlos (DEMa/UFSCar), SP (Brazil). Dept. de Engenharia de Materiais; Marques, R.F.C. [Universidade Federal de Alfenas (UNIFAL), Pocos de Caldas, MG (Brazil)

    2010-07-01

    Among the bioceramic hydroxyapatite (HAP) and beta-tricalcium phosphate (beta-TCP) are materials commonly used in biomedical field. Their combined properties result in a material with absorbable and at the same time with bioactive surface. Called biphasic ceramics such materials respond more quickly when exposed to physiological environment. In this work, powders of HAP/beta-TCP were obtained by chemical precipitation. After obtaining the post-phase was added at a ratio of 0, 15% and 30w% aqueous solutions of corn starch in order to obtain porous bodies. After mixing the resulting solutions were dried, resigned in tablet form and sintered at 1300 deg C. The initial powder was characterized by X-ray diffraction with Rietveld refinement to quantify the phases present. Bodies-of-evidence has been characterized by calculating the bulk density, X-ray diffraction (XRD), scanning electron microscopy and diametral compression. (author)

  14. Life threatening biphasic adverse reactions to desmopressin: case report and review of the literature.

    Science.gov (United States)

    Wang, Lijun; Chen, Ruijun; Tian, Fang; Wang, Wei; Wang, Li; Yu, Baojun; Huang, Xianwen; Zhang, Yuehui; Su, Shengyuan; Ma, Guangnian; Wang, Kaichen

    2016-08-01

    Treatment with desmopressin diacetate arginine vasopressin (DDAVP) and its withdrawal are associated with side effects. We present a rare case of severe biphasic adverse reactions induced by DDAVP and its withdrawal in a 63-year-old female patient. A lump in the left axillary region was biopsied, and she received DDAVP after surgery. The following day, she lost consciousness, with foaming at the mouth and seizures. Hypotonic encephalopathy was considered. DDAVP was ceased, and she received electrolytes. On day 1, she displayed low blood pressure and increased urine output. She received DDAVP and dopamine as well as electrolytes. The patient was ambulatory on day 7 and was discharged without brain abnormalities on MRI. In conclusion, severe hyponatremia induced by DDAVP and massive polyuria and hypovolemic shock induced by DDAVP withdrawal are life-threatening conditions. This case underlines the need to be vigilant when administering DDAVP and to monitor for any side effects. PMID:27142268

  15. Perfluorinated quaternary ammonium salts of polyoxometalate anions: Fluorous biphasic oxidation catalysis with and without fluorous solvents

    Energy Technology Data Exchange (ETDEWEB)

    Maayan, Galia; Fish, Richard H.; Neumann, Ronny

    2003-05-28

    Perfluorinated quaternary ammonium cations, [CF{sub 3}(CF{sub 2}){sub 7}(CH{sub 2}){sub 3}]{sub 3}CH{sub 3}N{sup +} (RFN{sup +}), were synthesized and used as counter cations for the [WZnM{sub 2}(H{sub 2}O){sub 2}(ZnW{sub 9}O{sub 34}){sub 2}]{sup 12-} (M = Mn(II), Zn(II)), polyoxometalate. The (RFN{sup +}){sub 12}[WZnM{sub 2}(H{sub 2}O){sub 2}(ZnW9O{sub 34}){sub 2}] compounds were fluorous biphasic catalysts for alcohol and alkenol oxidation, and alkene epoxidation with aqueous hydrogen peroxide. Reaction protocols with or without a fluorous solvent were tested. The catalytic activity and selectivity was affected both by the hydrophobicity of the solvent and the substrate.

  16. Microwave assisted synthesis & properties of nano HA-TCP biphasic calcium phosphate

    Science.gov (United States)

    Ghomash Pasand, E.; Nemati, A.; Solati-Hashjin, M.; Arzani, K.; Farzadi, A.

    2012-05-01

    Biphasic calcium phosphate (BCP) nanopowders were synthesized by using microwave and non-microwave irradiation assisted processes. The synthesized powders were pressed under a pressure of 90 MPa, and then were sintered at 1000-1200°C for 1 h. The mechanical properties of the samples were investigated. The formed phases and microstructures were characterized by X-ray diffraction (XRD) and scanning electron microscopy (SEM). The results showed that the synthesis time was shorter, along with a more homogeneous microstructure, when the microwave irradiation assisted method was applied. The compression strength and the Young's modulus of the samples synthesized with microwave irradiation were about 60 MPa and 3 GPa, but those of the samples synthesized without microwave irradiation were about 30 MPa and 2 GPa, respectively. XRD patterns of the microwave irradiation assisted and non-microwave irradiation assisted nanopowders showed the coexistence of hydroxyapatite (HA) and tricalcium phosphate (TCP) phases in the system.

  17. Multiple CaMKII Binding Modes to the Actin Cytoskeleton Revealed by Single-Molecule Imaging.

    Science.gov (United States)

    Khan, Shahid; Conte, Ianina; Carter, Tom; Bayer, K Ulrich; Molloy, Justin E

    2016-07-26

    Localization of the Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) to dendritic spine synapses is determined in part by the actin cytoskeleton. We determined binding of GFP-tagged CaMKII to tag-RFP-labeled actin cytoskeleton within live cells using total internal reflection fluorescence microscopy and single-molecule tracking. Stepwise photobleaching showed that CaMKII formed oligomeric complexes. Photoactivation experiments demonstrated that diffusion out of the evanescent field determined the track lifetimes. Latrunculin treatment triggered a coupled loss of actin stress fibers and the colocalized, long-lived CaMKII tracks. The CaMKIIα (α) isoform, which was previously thought to lack F-actin interactions, also showed binding, but this was threefold weaker than that observed for CaMKIIβ (β). The βE' splice variant bound more weakly than α, showing that binding by β depends critically on the interdomain linker. The mutations βT287D and αT286D, which mimic autophosphorylation states, also abolished F-actin binding. Autophosphorylation triggers autonomous CaMKII activity, but does not impair GluN2B binding, another important synaptic protein interaction of CaMKII. The CaMKII inhibitor tatCN21 or CaMKII mutations that inhibit GluN2B association by blocking binding of ATP (βK43R and αK42M) or Ca(2+)/calmodulin (βA303R) had no effect on the interaction with F-actin. These results provide the first rationale for the reduced synaptic spine localization of the αT286D mutant, indicating that transient F-actin binding contributes to the synaptic localization of the CaMKIIα isoform. The track lifetime distributions had a stretched exponential form consistent with a heterogeneously diffusing population. This heterogeneity suggests that CaMKII adopts different F-actin binding modes, which is most easily rationalized by multiple subunit contacts between the CaMKII dodecamer and the F-actin cytoskeleton that stabilize the initial weak (micromolar

  18. Sympathetically evoked Ca2+ signaling in arterial smooth muscle

    Institute of Scientific and Technical Information of China (English)

    Wei-jin ZANG; Joseph ZACHARIA; Christine LAMONT; Withrow Gil WIER

    2006-01-01

    The sympathetic nervous system plays an essential role in the control of total peripheral vascular resistance and blood flow, by controlling the contraction of small arteries. Perivascular sympathetic nerves release ATP, norepinephrine (NE) and neuropeptide Y. This review summarizes our knowledge of the intracellular Ca2+ signals that are activated by ATP and NE, acting respectively on P2X1 and α1 adrenoceptors in arterial smooth muscle. Each neurotransmitter produces a unique type of post-synaptic Ca2+ signal and associated contraction. The neural release of ATP and NE is thought to vary markedly with the pattern of nerve activity, probably reflecting both pre- and post-synaptic mechanisms. Finally, we show that Ca2+ signaling during neurogenic contractions activated by trains of sympathetic nerve fiber action potentials are in fact significantly different from that elicited by simple bath application of exogenous neurotransmitters to isolated arteries (a common experimental technique), and end by identifying important questions remaining in our understanding of sympathetic neurotransmission and the physiological regulation of contraction of small arteries.

  19. Frequent biphasic cellular responses of permanent fish cell cultures to deoxynivalenol (DON)

    International Nuclear Information System (INIS)

    Contamination of animal feed with mycotoxins is a major problem for fish feed mainly due to usage of contaminated ingredients for production and inappropriate storage of feed. The use of cereals for fish food production further increases the risk of a potential contamination. Potential contaminants include the mycotoxin deoxynivalenol (DON) which is synthesized by globally distributed fungi of the genus Fusarium. The toxicity of DON is well recognized in mammals. In this study, we confirm cytotoxic effects of DON in established permanent fish cell lines. We demonstrate that DON is capable of influencing the metabolic activity and cell viability in fish cells as determined by different assays to indicate possible cellular targets of this toxin. Evaluation of cell viability by measurement of membrane integrity, mitochondrial activity and lysosomal function after 24 h of exposure of fish cell lines to DON at a concentration range of 0-3000 ng ml-1 shows a biphasic effect on cells although differences in sensitivity occur. The cell lines derived from rainbow trout are particularly sensitive to DON. The focus of this study lies, furthermore, on the effects of DON at different concentrations on production of reactive oxygen species (ROS) in the different fish cell lines. The results show that DON mainly reduces ROS production in all cell lines that were used. Thus, our comparative investigations reveal that the fish cell lines show distinct species-related endpoint sensitivities that also depend on the type of tissue from which the cells were derived and the severity of exposure. - Highlights: → DON uptake by cells is not extensive. → All fish cell lines are sensitive to DON. → DON is most cytotoxic to rainbow trout cells. → Biphasic cellular responses were frequently observed. → Our results are similar to studies on mammalian cell lines.

  20. Biphasic cultivation strategy to avoid Epo-Fc aggregation and optimize protein expression.

    Science.gov (United States)

    Kaisermayer, Christian; Reinhart, David; Gili, Andreas; Chang, Martina; Aberg, Per-Mikael; Castan, Andreas; Kunert, Renate

    2016-06-10

    In biphasic cultivations, the culture conditions are initially kept at an optimum for rapid cell growth and biomass accumulation. In the second phase, the culture is shifted to conditions ensuring maximum specific protein production and the protein quality required. The influence of specific culture parameters is cell line dependent and their impact on product quality needs to be investigated. In this study, a biphasic cultivation strategy for a Chinese hamster ovary (CHO) cell line expressing an erythropoietin fusion protein (Epo-Fc) was developed. Cultures were run in batch mode and after an initial growth phase, cultivation temperature and pH were shifted. Applying a DoE (Design of Experiments) approach, a fractional factorial design was used to systematically evaluate the influence of cultivation temperature and pH as well as their synergistic effect on cell growth as well as on recombinant protein production and aggregation. All three responses were influenced by the cultivation temperature. Additionally, an interaction between pH and temperature was found to be related to protein aggregation. Compared with the initial standard conditions of 37°C and pH 7.05, a parameter shift to low temperature and acidic pH resulted in a decrease in the aggregate fraction from 75% to less than 1%. Furthermore, the synergistic effect of temperature and pH substantially lowered the cell-specific rates of glucose and glutamine consumption as well as lactate and ammonium production. The optimized culture conditions also led to an increase of the cell-specific rates of recombinant Epo-Fc production, thus resulting in a more economic bioprocess. PMID:27050504

  1. Biphasic quantum dots of cubic and hexagonal Mn doped CdS; necessity of Rietveld analysis

    Energy Technology Data Exchange (ETDEWEB)

    Heiba, Zein K., E-mail: zein_kh@yahoo.com [Ain Shams University, Faculty of Science, Physics Department, Cairo (Egypt); Taif University, Faculty of Science, Physics Department (Saudi Arabia); Mohamed, Mohamed Bakr [Ain Shams University, Faculty of Science, Physics Department, Cairo (Egypt); Imam, N.G. [Experimental Physics Department, Nuclear Research Center, Atomic Energy Authority, 13759 Cairo (Egypt)

    2015-01-05

    Highlights: • Mn{sup 2+} doped CdS quantum dots (QDs) were prepared via a simple chemical synthesis procedure. • Biphasic composite of CdS QDs was revealed with maximum magnetism at 10 at.% of Mn{sup 2+}. • Rietveld structural analysis is a necessity for dealing with nano or quantum dots chalcogenides. • Full investigation of effects of Mn doping on the structural, optical and magnetic parameters. - Abstract: Mn{sup 2+} doped CdS quantum dots (QDs) were prepared via a simple chemical synthesis method. Incorporation of Mn ions into CdS QDs was monitored by structural, magnetic and optical spectroscopy analysis. Although the diffraction patterns seemed to be single wurtzite hexagonal structure, analysis revealed biphasic composite of CdS QDs hexagonal wurtzite and cubic zinc blende. The band gap, crystal phase and the morphology of CdS QDs were found not to be greatly affected by Mn{sup 2+} doping, however there was an optimal Mn{sup 2+} doping content of 10% where the magnetism is maximum. The recorded photoluminescence (PL) emission spectra, excited at 370 nm, depict emission lines in the UV and blue-shift regions. The emission band reveals that the band gap of pure CdS QDs is around 3 eV which is greater than that of bulk CdS (2.42 eV). The band gap of Mn:CdS QDs is almost independent of Mn content (x) and the crystallite size remains almost the same for all values of x. The observed structural, magnetic and optical properties have been explained on the basis of formation of two phases of CdS doped with Mn. This work aims to highlight recent advances in the synthesis of Mn:CdS diluted magnetic semiconductor quantum dots and their wonderful performance.

  2. Regulation of the demographic structure in isomorphic biphasic life cycles at the spatial fine scale.

    Directory of Open Access Journals (Sweden)

    Vasco Manuel Nobre de Carvalho da Silva Vieira

    Full Text Available Isomorphic biphasic algal life cycles often occur in the environment at ploidy abundance ratios (Haploid:Diploid different from 1. Its spatial variability occurs within populations related to intertidal height and hydrodynamic stress, possibly reflecting the niche partitioning driven by their diverging adaptation to the environment argued necessary for their prevalence (evolutionary stability. Demographic models based in matrix algebra were developed to investigate which vital rates may efficiently generate an H:D variability at a fine spatial resolution. It was also taken into account time variation and type of life strategy. Ploidy dissimilarities in fecundity rates set an H:D spatial structure miss-fitting the ploidy fitness ratio. The same happened with ploidy dissimilarities in ramet growth whenever reproductive output dominated the population demography. Only through ploidy dissimilarities in looping rates (stasis, breakage and clonal growth did the life cycle respond to a spatially heterogeneous environment efficiently creating a niche partition. Marginal locations were more sensitive than central locations. Related results have been obtained experimentally and numerically for widely different life cycles from the plant and animal kingdoms. Spore dispersal smoothed the effects of ploidy dissimilarities in fertility and enhanced the effects of ploidy dissimilarities looping rates. Ploidy dissimilarities in spore dispersal could also create the necessary niche partition, both over the space and time dimensions, even in spatial homogeneous environments and without the need for conditional differentiation of the ramets. Fine scale spatial variability may be the key for the prevalence of isomorphic biphasic life cycles, which has been neglected so far.

  3. Rapid stimulus-evoked astrocyte Ca2+ elevations and hemodynamic responses in mouse somatosensory cortex in vivo

    DEFF Research Database (Denmark)

    Lind, Barbara Lykke; Brazhe, Alexey; Jessen, Sanne Barsballe;

    2013-01-01

    in astrocyte somas, processes, and end-feet preceded local vasodilatation. Fast Ca(2+) responses in both neurons and astrocytes correlated with synaptic activity, but only the astrocytic responses correlated with the hemodynamic shifts. These data establish that a large proportion of cortical astrocytes have...

  4. Fragile X Syndrome: Keys to the Molecular Genetics of Synaptic Plasticity

    Science.gov (United States)

    Lombroso, Paul J.; Ogren, Marilee P.

    2008-01-01

    Fragile X syndrome, the most common form of inherited mental retardation is discussed. The relationship between specific impairments in synaptic plasticity and Fragile X syndrome is investigated as it strengthens synaptic contacts between neurons.

  5. Quantitative Analysis of Synaptic Release at the Photoreceptor Synapse

    OpenAIRE

    Duncan, Gabriel; Rabl, Katalin; Gemp, Ian; Heidelberger, Ruth; Thoreson, Wallace B.

    2010-01-01

    Exocytosis from the rod photoreceptor is stimulated by submicromolar Ca2+ and exhibits an unusually shallow dependence on presynaptic Ca2+. To provide a quantitative description of the photoreceptor Ca2+ sensor for exocytosis, we tested a family of conventional and allosteric computational models describing the final Ca2+-binding steps leading to exocytosis. Simulations were fit to two measures of release, evoked by flash-photolysis of caged Ca2+: exocytotic capacitance changes from individua...

  6. Learning may need only a few bits of synaptic precision

    Science.gov (United States)

    Baldassi, Carlo; Gerace, Federica; Lucibello, Carlo; Saglietti, Luca; Zecchina, Riccardo

    2016-05-01

    Learning in neural networks poses peculiar challenges when using discretized rather then continuous synaptic states. The choice of discrete synapses is motivated by biological reasoning and experiments, and possibly by hardware implementation considerations as well. In this paper we extend a previous large deviations analysis which unveiled the existence of peculiar dense regions in the space of synaptic states which accounts for the possibility of learning efficiently in networks with binary synapses. We extend the analysis to synapses with multiple states and generally more plausible biological features. The results clearly indicate that the overall qualitative picture is unchanged with respect to the binary case, and very robust to variation of the details of the model. We also provide quantitative results which suggest that the advantages of increasing the synaptic precision (i.e., the number of internal synaptic states) rapidly vanish after the first few bits, and therefore that, for practical applications, only few bits may be needed for near-optimal performance, consistent with recent biological findings. Finally, we demonstrate how the theoretical analysis can be exploited to design efficient algorithmic search strategies.

  7. Cdk5 is essential for synaptic vesicle endocytosis

    DEFF Research Database (Denmark)

    Tan, Timothy C; Valova, Valentina A; Malladi, Chandra S;

    2003-01-01

    Synaptic vesicle endocytosis (SVE) is triggered by calcineurin-mediated dephosphorylation of the dephosphin proteins. SVE is maintained by the subsequent rephosphorylation of the dephosphins by unidentified protein kinases. Here, we show that cyclin-dependent kinase 5 (Cdk5) phosphorylates dynamin...

  8. Voltage-dependent amplification of synaptic inputs in respiratory motoneurones

    DEFF Research Database (Denmark)

    Enríquez Denton, M; Wienecke, Jacob; Zhang, Mengliang;

    2012-01-01

    Key points The processes whereby various excitatory and inhibitory inputs are integrated in spinal motoneurones during naturally occurring motor acts are not well understood, largely because there are amplifying mechanisms within the motoneurone that can control the effective strengths of the inp...... calcium channels, appears to make a very small contribution. Instead, modulation of synaptic currents (through NMDA channels) appears to be more important....

  9. How do astrocytes shape synaptic transmission? Insights from electrophysiology

    Directory of Open Access Journals (Sweden)

    Glenn eDallérac

    2013-10-01

    Full Text Available A major breakthrough in neuroscience has been the realization in the last decades that the dogmatic view of astroglial cells as being merely fostering and buffering elements of the nervous system is simplistic. A wealth of investigations now shows that astrocytes actually participate in the control of synaptic transmission in an active manner. This was first hinted by the intimate contacts glial processes make with neurons, particularly at the synaptic level, and evidenced using electrophysiological and calcium imaging techniques. Calcium imaging has provided critical evidence demonstrating that astrocytic regulation of synaptic efficacy is not a passive phenomenon. However, given that cellular activation is not only represented by calcium signaling, it is also crucial to assess concomitant mechanisms. We and others have used electrophysiological techniques to simultaneously record neuronal and astrocytic activity, thus enabling the study of multiple ionic currents and in depth investigation of neuro-glial dialogues. In the current review, we focus on the input such approach has provided in the understanding of astrocyte-neuron interactions underlying control of synaptic efficacy.

  10. Learning may need only a few bits of synaptic precision.

    Science.gov (United States)

    Baldassi, Carlo; Gerace, Federica; Lucibello, Carlo; Saglietti, Luca; Zecchina, Riccardo

    2016-05-01

    Learning in neural networks poses peculiar challenges when using discretized rather then continuous synaptic states. The choice of discrete synapses is motivated by biological reasoning and experiments, and possibly by hardware implementation considerations as well. In this paper we extend a previous large deviations analysis which unveiled the existence of peculiar dense regions in the space of synaptic states which accounts for the possibility of learning efficiently in networks with binary synapses. We extend the analysis to synapses with multiple states and generally more plausible biological features. The results clearly indicate that the overall qualitative picture is unchanged with respect to the binary case, and very robust to variation of the details of the model. We also provide quantitative results which suggest that the advantages of increasing the synaptic precision (i.e., the number of internal synaptic states) rapidly vanish after the first few bits, and therefore that, for practical applications, only few bits may be needed for near-optimal performance, consistent with recent biological findings. Finally, we demonstrate how the theoretical analysis can be exploited to design efficient algorithmic search strategies. PMID:27300916

  11. Dynamic microtubules regulate dendritic spine morphology and synaptic plasticity

    NARCIS (Netherlands)

    J. Jaworski; L.C. Kapitein; S. Montenegro Gouveia; B.R. Dortland; P.S. Wulf; I. Grigoriev; P. Camera; S.A. Spangler; P. Di Stefano; J. Demmers; H. Krugers; P. Defilippi; A. Akhmanova; C.C. Hoogenraad

    2009-01-01

    Dendritic spines are the major sites of excitatory synaptic input, and their morphological changes have been linked to learning and memory processes. Here, we report that growing microtubule plus ends decorated by the microtubule tip-tracking protein EB3 enter spines and can modulate spine morpholog

  12. Translational regulatory mechanisms in persistent forms of synaptic plasticity.

    Science.gov (United States)

    Kelleher, Raymond J; Govindarajan, Arvind; Tonegawa, Susumu

    2004-09-30

    Memory and synaptic plasticity exhibit distinct temporal phases, with long-lasting forms distinguished by their dependence on macromolecular synthesis. Prevailing models for the molecular mechanisms underlying long-lasting synaptic plasticity have largely focused on transcriptional regulation. However, a growing body of evidence now supports a crucial role for neuronal activity-dependent mRNA translation, which may occur in dendrites for a subset of neuronal mRNAs. Recent work has begun to define the signaling mechanisms coupling synaptic activation to the protein synthesis machinery. The ERK and mTOR signaling pathways have been shown to regulate the activity of the general translational machinery, while the translation of particular classes of mRNAs is additionally controlled by gene-specific mechanisms. Rapid enhancement of the synthesis of a diverse array of neuronal proteins through such mechanisms provides the components necessary for persistent forms of LTP and LTD. These findings have important implications for the synapse specificity and associativity of protein synthesis-dependent changes in synaptic strength. PMID:15450160

  13. Isoform Specificity of Protein Kinase Cs in Synaptic Plasticity

    Science.gov (United States)

    Sossin, Wayne S.

    2007-01-01

    Protein kinase Cs (PKCs) are implicated in many forms of synaptic plasticity. However, the specific isoform(s) of PKC that underlie(s) these events are often not known. We have used "Aplysia" as a model system in order to investigate the isoform specificity of PKC actions due to the presence of fewer isoforms and a large number of documented…

  14. Falling towards forgetfulness: synaptic decay prevents spontaneous recovery of memory.

    Directory of Open Access Journals (Sweden)

    James V Stone

    Full Text Available Long after a new language has been learned and forgotten, relearning a few words seems to trigger the recall of other words. This "free-lunch learning" (FLL effect has been demonstrated both in humans and in neural network models. Specifically, previous work proved that linear networks that learn a set of associations, then partially forget them all, and finally relearn some of the associations, show improved performance on the remaining (i.e., nonrelearned associations. Here, we prove that relearning forgotten associations decreases performance on nonrelearned associations; an effect we call negative free-lunch learning. The difference between free-lunch learning and the negative free-lunch learning presented here is due to the particular method used to induce forgetting. Specifically, if forgetting is induced by isotropic drifting of weight vectors (i.e., by adding isotropic noise, then free-lunch learning is observed. However, as proved here, if forgetting is induced by weight values that simply decay or fall towards zero, then negative free-lunch learning is observed. From a biological perspective, and assuming that nervous systems are analogous to the networks used here, this suggests that evolution may have selected physiological mechanisms that involve forgetting using a form of synaptic drift rather than synaptic decay, because synaptic drift, but not synaptic decay, yields free-lunch learning.

  15. Spontaneous Activity Drives Local Synaptic Plasticity In Vivo

    NARCIS (Netherlands)

    Winnubst, Johan; Cheyne, Juliette E; Niculescu, Dragos; Lohmann, C.

    2015-01-01

    Spontaneous activity fine-tunes neuronal connections in the developing brain. To explore the underlying synaptic plasticity mechanisms, we monitored naturally occurring changes in spontaneous activity at individual synapses with whole-cell patch-clamp recordings and simultaneous calcium imaging in t

  16. Spontaneous Activity Drives Local Synaptic Plasticity In Vivo.

    Science.gov (United States)

    Winnubst, Johan; Cheyne, Juliette E; Niculescu, Dragos; Lohmann, Christian

    2015-07-15

    Spontaneous activity fine-tunes neuronal connections in the developing brain. To explore the underlying synaptic plasticity mechanisms, we monitored naturally occurring changes in spontaneous activity at individual synapses with whole-cell patch-clamp recordings and simultaneous calcium imaging in the mouse visual cortex in vivo. Analyzing activity changes across large populations of synapses revealed a simple and efficient local plasticity rule: synapses that exhibit low synchronicity with nearby neighbors (depressed in their transmission frequency. Asynchronous electrical stimulation of individual synapses in hippocampal slices showed that this is due to a decrease in synaptic transmission efficiency. Accordingly, experimentally increasing local synchronicity, by stimulating synapses in response to spontaneous activity at neighboring synapses, stabilized synaptic transmission. Finally, blockade of the high-affinity proBDNF receptor p75(NTR) prevented the depression of asynchronously stimulated synapses. Thus, spontaneous activity drives local synaptic plasticity at individual synapses in an "out-of-sync, lose-your-link" fashion through proBDNF/p75(NTR) signaling to refine neuronal connectivity. VIDEO ABSTRACT. PMID:26182421

  17. The Role of Short Term Synaptic Plasticity in Temporal Coding of Neuronal Networks

    Science.gov (United States)

    Chandrasekaran, Lakshmi

    2008-01-01

    Short term synaptic plasticity is a phenomenon which is commonly found in the central nervous system. It could contribute to functions of signal processing namely, temporal integration and coincidence detection by modulating the input synaptic strength. This dissertation has two parts. First, we study the effects of short term synaptic plasticity…

  18. Up-regulation of GLT-1 severely impairs LTD at mossy fibre--CA3 synapses.

    Science.gov (United States)

    Omrani, Azar; Melone, Marcello; Bellesi, Michele; Safiulina, Victoria; Aida, Tomomi; Tanaka, Kohishi; Cherubini, Enrico; Conti, Fiorenzo

    2009-10-01

    Glutamate transporters are responsible for clearing synaptically released glutamate from the extracellular space. By this action, they maintain low levels of ambient glutamate, thus preventing excitotoxic damage, and contribute to shaping synaptic currents. We show that up-regulation of the glutamate transporter GLT-1 by ceftriaxone severely impaired mGluR-dependent long-term depression (LTD), induced at rat mossy fibre (MF)-CA3 synapses by repetitive stimulation of afferent fibres. This effect involved GLT-1, since LTD was rescued by the selective GLT-1 antagonist dihydrokainate (DHK). DHK per se produced a modest decrease in fEPSP amplitude that rapidly regained control levels after DHK wash out. Moreover, the degree of fEPSP inhibition induced by the low-affinity glutamate receptor antagonist gamma-DGG was similar during basal synaptic transmission but not during LTD, indicating that in ceftriaxone-treated rats LTD induction did not alter synaptic glutamate transient concentration. Furthermore, ceftriaxone-induced GLT-1 up-regulation significantly reduced the magnitude of LTP at MF-CA3 synapses but not at Schaffer collateral-CA1 synapses. Postembedding immunogold studies in rats showed an increased density of gold particles coding for GLT-1a in astrocytic processes and in mossy fibre terminals; in the latter, gold particles were located near and within the active zones. In both CEF-treated and untreated GLT-1 KO mice used for verifying the specificity of immunostaining, the density of gold particles in MF terminals was comparable to background levels. The enhanced expression of GLT-1 at release sites may prevent activation of presynaptic receptors, thus revealing a novel mechanism by which GLT-1 regulates synaptic plasticity in the hippocampus.

  19. The Role of GluK4 in Synaptic Plasticity and Affective Behavior in Mice

    Science.gov (United States)

    Catches, Justin Samuel

    Kainate receptors (KARs) are glutamate-gated ion channels that signal through both ionotropic and metabotropic pathways (Contractor et al., 2011). Combinations of five KAR subunits (GluK1-5) form tetrameric receptors with GluK1, GluK2, and GluK3 able to form functional homomeric channels. The high-affinity subunits, GluK4 and GluK5, do not form homomeric channels but modify the properties of heteromeric receptors. Expression of the GluK4 receptor subunit in the forebrain is restricted to the CA3 region of the hippocampus and dentate gyrus regions where KARs modulate synaptic plasticity. In this study, ablation of Grik4, which encodes GluK4, in mice reduced KAR synaptic currents and altered activation properties of postsynaptic receptors but left two forms of presynaptic short-term plasticity intact. Disruption of both Grik4 and Grik5 caused complete loss of the postsynaptic ionotropic KAR current and impaired presynaptic frequency facilitation. Additionally, KAR surface expression was altered at pre- and postsynaptic sites at the MF synapse. Despite the loss of ionotropic signaling, KAR-mediated inhibition of the slow afterhyperpolarization current, which is dependent on metabotropic signaling, was intact in CA3 neurons. Long-term potentiation at the MF-CA3 synapse was reduced, likely through a loss of KAR modulation of excitability of the presynaptic MF axons. Genetic variants in the human GRIK4 gene alter the susceptibility for affective disorders (Bloss and Hunter, 2010). We found that ablation of Grik4 in mice resulted in reduced anxiety and an antidepressant-like phenotype. In the elevated zero-maze, a test for anxiety and risk taking behavior, and in two anxiogenic tests, marble-burying and novelty-induced suppression of feeding, anxiety-like behavior was consistently reduced in knockout animals. In the forced swim, a test of learned helplessness used to determine depression-like behavior, knockout mice demonstrated significantly less immobility suggesting

  20. Regulation by L channels of Ca(2+)-evoked secretory responses in ouabain-treated chromaffin cells.

    Science.gov (United States)

    De Pascual, Ricardo; Colmena, Inés; Ruiz-Pascual, Lucía; Baraibar, Andrés Mateo; Egea, Javier; Gandía, Luis; García, Antonio G

    2016-10-01

    It is known that the sustained depolarisation of adrenal medullary bovine chromaffin cells (BCCs) with high K(+) concentrations produces an initial sharp catecholamine release that subsequently fades off in spite depolarisation persists. Here, we have recreated a sustained depolarisation condition of BCCs by treating them with the Na(+)/K(+) ATPase blocker ouabain; in doing so, we searched experimental conditions that permitted the development of a sustained long-term catecholamine release response that could be relevant during prolonged stress. BCCs were perifused with nominal 0Ca(2+) solution, and secretion responses were elicited by intermittent application of short 2Ca(2+) pulses (Krebs-HEPES containing 2 mM Ca(2+)). These pulses elicited a biphasic secretory pattern with an initial 30-min period with secretory responses of increasing amplitude and a second 30-min period with steady-state, non-inactivating responses. The initial phase was not due to gradual depolarisation neither to gradual increases of the cytosolic calcium transients ([Ca(2+)]c) elicited by 2Ca(2+) pulses in BBCs exposed to ouabain; both parameters increased soon after ouabain addition. Νifedipine blocked these responses, and FPL64176 potentiated them, suggesting that they were triggered by Ca(2+) entry through non-inactivating L-type calcium channels. This was corroborated by nifedipine-evoked blockade of the L-type Ca(2+) channel current and the [Ca(2+)]c transients elicited by 2Ca(2+) pulses. Furthermore, the plasmalemmal Na(+)/Ca(2+) exchanger (NCX) blocker SEA0400 caused a mild inhibition followed by a large rebound increase of the steady-state secretory responses. We conclude that these two phases of secretion are mostly contributed by Ca(2+) entry through L calcium channels, with a minor contribution of Ca(2+) entry through the reverse mode of the NCX.

  1. Synaptic plasticity and gravity: Ultrastructural, biochemical and physico-chemical fundamentals

    Science.gov (United States)

    Rahmann, H.; Slenzka, K.; Körtje, K. H.; Hilbig, R.

    On the basis of quantitative disturbances of the swimming behaviour of aquatic vertebrates (``loop-swimming'' in fish and frog larvae) following long-term hyper-g-exposure the question was raised whether or not and to what extent changes in the gravitational vector might influence the CNS at the cellular level. Therefore, by means of histological, histochemical and biochemical analyses the effect of 2-4 x g for 9 days on the gross morphology of the fish brain, and on different neuronal enzymes was investigated. In order to enable a more precise analysis in future-μg-experiments of any gravity-related effects on the neuronal synapses within the gravity-perceptive integration centers differentiated electron-microscopical and electronspectroscopical techniques have been developed to accomplish an ultrastructural localization of calcium, a high-affinity Ca2+-ATPase, creatine kinase and cytochrome oxidase. In hyper-g animals vs. 1-g controls, a reduction of total brain volume (15 %), a decrease in creatine kinase activity (20 %), a local increase in cytochrome oxidase activity, but no differences in Ca2+/Mg2+-ATPase activities were observed. Ultrastructural peculiarities of synaptic contact formation in gravity-related integration centers (Nucleus magnocellularis) were found. These results are discussed on the basis of a direct effect of hyper-gravity not only on the gravity-sensitive neuronal integration centers but possibly also on the physico-chemical properties of the lipid bilayer of neuronal membranes in general.

  2. p38 MAPK Inhibition Improves Synaptic Plasticity and Memory in Angiotensin II-dependent Hypertensive Mice

    Science.gov (United States)

    Dai, Hai-long; Hu, Wei-yuan; Jiang, Li-hong; Li, Le; Gaung, Xue-feng; Xiao, Zhi-cheng

    2016-01-01

    The pathogenesis of hypertension-related cognitive impairment has not been sufficiently clarified, new molecular targets are needed. p38 MAPK pathway plays an important role in hypertensive target organ damage. Activated p38 MAPK was seen in AD brain tissue. In this study, we found that long-term potentiation (LTP) of hippocampal CA1 was decreased, the density of the dendritic spines on the CA1 pyramidal cells was reduced, the p-p38 protein expression in hippocampus was elevated, and cognitive function was impaired in angiotensin II-dependent hypertensive C57BL/6 mice. In vivo, using a p38 heterozygous knockdown mice (p38KI/+) model, we showed that knockdown of p38 MAPK in hippocampus leads to the improvement of cognitive function and hippocampal synaptic plasticity in angiotensin II-dependent p38KI/+ hypertensive mice. In vitro, LTP was improved in hippocampal slices from C57BL/6 hypertensive mice by treatment with p38MAPK inhibitor SKF86002. Our data demonstrated that p38 MAPK may be a potential therapeutic target for hypertension-related cognitive dysfunction. PMID:27283322

  3. Ca2+ entry in gonadotrophs and alpha T3-1 cells: does store-dependent Ca2+ influx mediate gonadotrophin-releasing hormone action?

    Science.gov (United States)

    McArdle, C A; Forrest-Owen, W; Davidson, J S; Fowkes, R; Bunting, R; Mason, W T; Poch, A; Kratzmeier, M

    1996-04-01

    In pituitary gonadotrophs GnRH causes biphasic (spike and plateau) increases in cytosolic Ca2+ ([Ca2+]i) and gonadotrophin release. The spike phases reflect mobilization of stored Ca2+ and the plateau responses are attributed, in part, to Ca2+ influx via voltage-sensitive Ca2+ channels. In recent years, store-dependent Ca2+ influx (SDCI), in which depletion of the intracellular inositol 1,4,5-trisphosphate-mobilizable pool stimulates Ca2+ influx, has emerged as a major form of Ca2+ entry activated by phosphoinositidase C-coupled receptors in non-excitable cells. More recent evidence also indicates a role for SDCI in excitable cells. We have used dynamic video imaging of [Ca2+]i in alpha T3-1 cells (a gonadotroph-derived cell line) and manipulation of the filling state of the GnRH-mobilizable Ca2+ pool to test the possible role of SDCI in GnRH action. In Ca(2+)-containing medium, GnRH caused a biphasic increase in [Ca2+]i whereas in Ca(2+)-free medium only a transient increase occurred. The response to a second stimulation with GnRH in Ca(2+)-free medium was reduced by > 95% (demonstrating that Ca2+ pool depletion had occurred) and was recovered after brief exposure to Ca(2+)-containing medium (which enables refilling of the pool). Ionomycin (a Ca2+ ionophore) and thapsigargin (which inhibits the Ca(2+)-sequestering ATPase of the endoplasmic reticulum) also transiently increased [Ca2+]i in Ca(2+)-free medium and depleted the GnRH-mobilizable pool as indicated by greatly reduced subsequent responses to GnRH. Pool depletion also occurs on stimulation with GnRH in Ca(2+)-containing medium because addition of ionomycin and Ca(2+)-free medium during the plateau phase of the GnRH response caused only a reduction in [Ca2+]i rather than the transient increase seen without GnRH. To deplete intracellular Ca2+ pools, cells were pretreated in Ca(2+)-free medium with thapsigargin or GnRH and then, after extensive washing, returned to Ca(2+)-containing medium. Pretreatment with

  4. Ablation of NMDA receptors enhances the excitability of hippocampal CA3 neurons.

    Directory of Open Access Journals (Sweden)

    Fumiaki Fukushima

    Full Text Available Synchronized discharges in the hippocampal CA3 recurrent network are supposed to underlie network oscillations, memory formation and seizure generation. In the hippocampal CA3 network, NMDA receptors are abundant at the recurrent synapses but scarce at the mossy fiber synapses. We generated mutant mice in which NMDA receptors were abolished in hippocampal CA3 pyramidal neurons by postnatal day 14. The histological and cytological organizations of the hippocampal CA3 region were indistinguishable between control and mutant mice. We found that mutant mice lacking NMDA receptors selectively in CA3 pyramidal neurons became more susceptible to kainate-induced seizures. Consistently, mutant mice showed characteristic large EEG spikes associated with multiple unit activities (MUA, suggesting enhanced synchronous firing of CA3 neurons. The electrophysiological balance between fast excitatory and inhibitory synaptic transmission was comparable between control and mutant pyramidal neurons in the hippocampal CA3 region, while the NMDA receptor-slow AHP coupling was diminished in the mutant neurons. In the adult brain, inducible ablation of NMDA receptors in the hippocampal CA3 region by the viral expression vector for Cre recombinase also induced similar large EEG spikes. Furthermore, pharmacological blockade of CA3 NMDA receptors enhanced the susceptibility to kainate-induced seizures. These results raise an intriguing possibility that hippocampal CA3 NMDA receptors may suppress the excitability of the recurrent network as a whole in vivo by restricting synchronous firing of CA3 neurons.

  5. Salvia miltiorrhiza Bunge Blocks Ethanol-Induced Synaptic Dysfunction through Regulation of NMDA Receptor-Dependent Synaptic Transmission.

    Science.gov (United States)

    Park, Hye Jin; Lee, Seungheon; Jung, Ji Wook; Lee, Young Choon; Choi, Seong-Min; Kim, Dong Hyun

    2016-07-01

    Consumption of high doses of ethanol can lead to amnesia, which often manifests as a blackout. These blackouts experienced by ethanol consumers may be a major cause of the social problems associated with excess ethanol consumption. However, there is currently no established treatment for preventing these ethanol-induced blackouts. In this study, we tested the ethanol extract of the roots of Salvia miltiorrhiza (SM) for its ability to mitigate ethanol-induced behavioral and synaptic deficits. To test behavioral deficits, an object recognition test was conducted in mouse. In this test, ethanol (1 g/kg, i.p.) impaired object recognition memory, but SM (200 mg/kg) prevented this impairment. To evaluate synaptic deficits, NMDA receptor-mediated excitatory postsynaptic potential (EPSP) and long-term potentiation (LTP) in the mouse hippocampal slices were tested, as they are known to be vulnerable to ethanol and are associated with ethanol-induced amnesia. SM (10 and 100 μg/ml) significantly ameliorated ethanol-induced long-term potentiation and NMDA receptor-mediated EPSP deficits in the hippocampal slices. Therefore, these results suggest that SM prevents ethanol-induced amnesia by protecting the hippocampus from NMDA receptor-mediated synaptic transmission and synaptic plasticity deficits induced by ethanol. PMID:27257009

  6. Odor-Specific Habituation Arises from Interaction of Afferent Synaptic Adaptation and Intrinsic Synaptic Potentiation in Olfactory Cortex

    Science.gov (United States)

    Linster, Christiane; Menon, Alka V.; Singh, Christopher Y.; Wilson, Donald A.

    2009-01-01

    Segmentation of target odorants from background odorants is a fundamental computational requirement for the olfactory system and is thought to be behaviorally mediated by olfactory habituation memory. Data from our laboratory have shown that odor-specific adaptation in piriform neurons, mediated at least partially by synaptic adaptation between…

  7. Axonal accumulation of synaptic markers in APP transgenic Drosophila depends on the NPTY motif and is paralleled by defects in synaptic plasticity

    DEFF Research Database (Denmark)

    Rusu, Patricia; Jansen, Anna; Soba, Peter;

    2007-01-01

    neurotransmission at the neuromuscular junction in transgenic larvae that express human APP. Consistent with the observation that these larvae do not show any obvious movement deficits, we found no changes in basal synaptic transmission. However, short-term synaptic plasticity was affected by overexpression of APP....... Together, our results show that overexpression of APP induces partial stalling of axonal transport vesicles, paralleled by abnormalities in synaptic plasticity, which may provide a functional link to the deterioration of cognitive functions observed in AD....

  8. Synaptic Targets of Medial Septal Projections in the Hippocampus and Extrahippocampal Cortices of the Mouse.

    Science.gov (United States)

    Unal, Gunes; Joshi, Abhilasha; Viney, Tim J; Kis, Viktor; Somogyi, Peter

    2015-12-01

    Temporal coordination of neuronal assemblies among cortical areas is essential for behavioral performance. GABAergic projections from the medial septum and diagonal band complex exclusively innervate GABAergic interneurons in the rat hippocampus, contributing to the coordination of neuronal activity, including the generation of theta oscillations. Much less is known about the synaptic target neurons outside the hippocampus. To reveal the contribution of synaptic circuits involving the medial septum of mice, we have identified postsynaptic cortical neurons in wild-type and parvalbumin-Cre knock-in mice. Anterograde axonal tracing from the septum revealed extensive innervation of the hippocampus as well as the subiculum, presubiculum, parasubiculum, the medial and lateral entorhinal cortices, and the retrosplenial cortex. In all examined cortical regions, many septal GABAergic boutons were in close apposition to somata or dendrites immunopositive for interneuron cell-type molecular markers, such as parvalbumin, calbindin, calretinin, N-terminal EF-hand calcium-binding protein 1, cholecystokinin, reelin, or a combination of these molecules. Electron microscopic observations revealed septal boutons forming axosomatic or axodendritic type II synapses. In the CA1 region of hippocampus, septal GABAergic projections exclusively targeted interneurons. In the retrosplenial cortex, 93% of identified postsynaptic targets belonged to interneurons and the rest to pyramidal cells. These results suggest that the GABAergic innervation from the medial septum and diagonal band complex contributes to temporal coordination of neuronal activity via several types of cortical GABAergic interneurons in both hippocampal and extrahippocampal cortices. Oscillatory septal neuronal firing at delta, theta, and gamma frequencies may phase interneuron activity. PMID:26631464

  9. Long-term potentiation modulates synaptic phosphorylation networks and reshapes the structure of the postsynaptic interactome.

    Science.gov (United States)

    Li, Jing; Wilkinson, Brent; Clementel, Veronica A; Hou, Junjie; O'Dell, Thomas J; Coba, Marcelo P

    2016-01-01

    The postsynaptic site of neurons is composed of more than 1500 proteins arranged in protein-protein interaction complexes, the composition of which is modulated by protein phosphorylation through the actions of complex signaling networks. Components of these networks function as key regulators of synaptic plasticity, in particular hippocampal long-term potentiation (LTP). The postsynaptic density (PSD) is a complex multicomponent structure that includes receptors, enzymes, scaffold proteins, and structural proteins. We triggered LTP in the mouse hippocampus CA1 region and then performed large-scale analyses to identify phosphorylation-mediated events in the PSD and changes in the protein-protein interactome of the PSD that were associated with LTP induction. Our data indicated LTP-induced reorganization of the PSD. The dynamic reorganization of the PSD links glutamate receptor signaling to kinases (writers) and phosphatases (erasers), as well as the target proteins that are modulated by protein phosphorylation and the proteins that recognize the phosphorylation status of their binding partners (readers). Protein phosphorylation and protein interaction networks converged at highly connected nodes within the PSD network. Furthermore, the LTP-regulated phosphoproteins, which included the scaffold proteins Shank3, Syngap1, Dlgap1, and Dlg4, represented the "PSD risk" for schizophrenia and autism spectrum disorder, such that without these proteins in the analysis, the association with the PSD and these two psychiatric diseases was not present. These data are a rich resource for future studies of LTP and suggest that the PSD holds the keys to understanding the molecular events that contribute to complex neurological disorders that affect synaptic plasticity. PMID:27507650

  10. Effects of ethanol on glycinergic synaptic currents in mouse spinal cord neurons

    Science.gov (United States)

    Mariqueo, Trinidad A.; Agurto, Adolfo; Muñoz, Braulio; San Martin, Loreto; Coronado, Cesar; Fernández-Pérez, Eduardo J.; Murath, Pablo; Sánchez, Andrea; Homanics, Gregg E.

    2014-01-01

    Ethanol increased the frequency of miniature glycinergic currents [miniature inhibitory postsynaptic currents (mIPSCs)] in cultured spinal neurons. This effect was dependent on intracellular calcium augmentation, since preincubation with BAPTA (an intracellular calcium chelator) or thapsigargin [a sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) pump inhibitor] significantly attenuated this effect. Similarly, U73122 (a phospholipase C inhibitor) or 2-aminoethoxydiphenyl borate [2-APB, an inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) inhibitor] reduced this effect. Block of ethanol action was also achieved after preincubation with Rp-cAMPS, inhibitor of the adenylate cyclase (AC)/PKA signaling pathway. These data suggest that there is a convergence at the level of IP3R that accounts for presynaptic ethanol effects. At the postsynaptic level, ethanol increased the decay time constant of mIPSCs in a group of neurons (30 ± 10% above control, n = 13/26 cells). On the other hand, the currents activated by exogenously applied glycine were consistently potentiated (55 ± 10% above control, n = 11/12 cells), which suggests that ethanol modulates synaptic and nonsynaptic glycine receptors (GlyRs) in a different fashion. Supporting the role of G protein modulation on ethanol responses, we found that a nonhydrolyzable GTP analog [guanosine 5′-O-(3-thiotriphosphate) (GTPγS)] increased the decay time constant in ∼50% of the neurons (28 ± 12%, n = 11/19 cells) but potentiated the glycine-activated Cl− current in most of the neurons examined (83 ± 29%, n = 7/9 cells). In addition, confocal microscopy showed that α1-containing GlyRs colocalized with Gβ and Piccolo (a presynaptic cytomatrix protein) in ∼40% of synaptic receptor clusters, suggesting that colocalization of Gβγ and GlyRs might account for the difference in ethanol sensitivity at the postsynaptic level. PMID:24572089

  11. A tale of two stories: astrocyte regulation of synaptic depression and facilitation.

    Directory of Open Access Journals (Sweden)

    Maurizio De Pittà

    2011-12-01

    Full Text Available Short-term presynaptic plasticity designates variations of the amplitude of synaptic information transfer whereby the amount of neurotransmitter released upon presynaptic stimulation changes over seconds as a function of the neuronal firing activity. While a consensus has emerged that the resulting decrease (depression and/or increase (facilitation of the synapse strength are crucial to neuronal computations, their modes of expression in vivo remain unclear. Recent experimental studies have reported that glial cells, particularly astrocytes in the hippocampus, are able to modulate short-term plasticity but the mechanism of such a modulation is poorly understood. Here, we investigate the characteristics of short-term plasticity modulation by astrocytes using a biophysically realistic computational model. Mean-field analysis of the model, supported by intensive numerical simulations, unravels that astrocytes may mediate counterintuitive effects. Depending on the expressed presynaptic signaling pathways, astrocytes may globally inhibit or potentiate the synapse: the amount of released neurotransmitter in the presence of the astrocyte is transiently smaller or larger than in its absence. But this global effect usually coexists with the opposite local effect on paired pulses: with release-decreasing astrocytes most paired pulses become facilitated, namely the amount of neurotransmitter released upon spike i+1 is larger than that at spike i, while paired-pulse depression becomes prominent under release-increasing astrocytes. Moreover, we show that the frequency of astrocytic intracellular Ca(2+ oscillations controls the effects of the astrocyte on short-term synaptic plasticity. Our model explains several experimental observations yet unsolved, and uncovers astrocytic gliotransmission as a possible transient switch between short-term paired-pulse depression and facilitation. This possibility has deep implications on the processing of neuronal spikes

  12. High-fat diet induces hepatic insulin resistance and impairment of synaptic plasticity.

    Directory of Open Access Journals (Sweden)

    Zhigang Liu

    Full Text Available High-fat diet (HFD-induced obesity is associated with insulin resistance, which may affect brain synaptic plasticity through impairment of insulin-sensitive processes underlying neuronal survival, learning, and memory. The experimental model consisted of 3 month-old C57BL/6J mice fed either a normal chow diet (control group or a HFD (60% of calorie from fat; HFD group for 12 weeks. This model was characterized as a function of time in terms of body weight, fasting blood glucose and insulin levels, HOMA-IR values, and plasma triglycerides. IRS-1/Akt pathway was assessed in primary hepatocytes and brain homogenates. The effect of HFD in brain was assessed by electrophysiology, input/output responses and long-term potentiation. HFD-fed mice exhibited a significant increase in body weight, higher fasting glucose- and insulin levels in plasma, lower glucose tolerance, and higher HOMA-IR values. In liver, HFD elicited (a a significant decrease of insulin receptor substrate (IRS-1 phosphorylation on Tyr608 and increase of Ser307 phosphorylation, indicative of IRS-1 inactivation; (b these changes were accompanied by inflammatory responses in terms of increases in the expression of NFκB and iNOS and activation of the MAP kinases p38 and JNK; (c primary hepatocytes from mice fed a HFD showed decreased cellular oxygen consumption rates (indicative of mitochondrial functional impairment; this can be ascribed partly to a decreased expression of PGC1α and mitochondrial biogenesis. In brain, HFD feeding elicited (a an inactivation of the IRS-1 and, consequentially, (b a decreased expression and plasma membrane localization of the insulin-sensitive neuronal glucose transporters GLUT3/GLUT4; (c a suppression of the ERK/CREB pathway, and (d a substantial decrease in long-term potentiation in the CA1 region of hippocampus (indicative of impaired synaptic plasticity. It may be surmised that 12 weeks fed with HFD induce a systemic insulin resistance that impacts

  13. PRRT2 Is a Key Component of the Ca2+-Dependent Neurotransmitter Release Machinery

    Directory of Open Access Journals (Sweden)

    Pierluigi Valente

    2016-04-01

    Full Text Available Heterozygous mutations in proline-rich transmembrane protein 2 (PRRT2 underlie a group of paroxysmal disorders, including epilepsy, kinesigenic dyskinesia, and migraine. Most of the mutations lead to impaired PRRT2 expression, suggesting that loss of PRRT2 function may contribute to pathogenesis. We show that PRRT2 is enriched in presynaptic terminals and that its silencing decreases the number of synapses and increases the number of docked synaptic vesicles at rest. PRRT2-silenced neurons exhibit a severe impairment of synchronous release, attributable to a sharp decrease in release probability and Ca2+ sensitivity and associated with a marked increase of the asynchronous/synchronous release ratio. PRRT2 interacts with the synaptic proteins SNAP-25 and synaptotagmin 1/2. The results indicate that PRRT2 is intimately connected with the Ca2+-sensing machinery and that it plays an important role in the final steps of neurotransmitter release.

  14. Effects of electromagnetic radiation on spatial memory and synapses in rat hippocampal CA1

    Institute of Scientific and Technical Information of China (English)

    Yuhong Li; Changhua Shi; Guobing Lu; Qian Xu; Shaochen Liu

    2012-01-01

    In this study, we investigated the effects of mobile phone radiation on spatial learning, reference memory, and morphology in related brain regions. After the near-field radiation (0.52-1.08 W/kg) was delivered to 8-week-old Wistar rats 2 hours per day for 1 month, behavioral changes were examined using the Morris water maze. Compared with the sham-irradiated rats, the irradiated rats exhibited impaired performance. Morphological changes were investigated by examining synaptic ultrastructural changes in the hippocampus. Using the physical dissector technique, the number of pyramidal neurons, the synaptic profiles, and the length of postsynaptic densities in the CA1 region were quantified stereologically. The morphological changes included mitochondrial degenerations, fewer synapses, and shorter postsynaptic densities in the radiated rats. These findings indicate that mobile phone radiation can significantly impair spatial learning and reference memory and induce morphological changes in the hippocampal CA1 region.

  15. Regulation of hippocampal synaptic plasticity thresholds and changes in exploratory and learning behavior in dominant negative NPR-B mutant rats

    Directory of Open Access Journals (Sweden)

    Gleb eBarmashenko

    2014-12-01

    Full Text Available The second messenger cyclic GMP affects synaptic transmission and modulates synaptic plasticity and certain types of learning and memory processes. The impact of the natriuretic peptide receptor B (NPR-B and its ligand C-type natriuretic peptide (CNP, one of several cGMP producing signalling systems, on hippocampal synaptic plasticity and learning is, however, less well understood. We have previously shown that the NPR-B ligand CNP increases the magnitude of long-term depression (LTD in hippocampal area CA1, while reducing the induction of long-term potentiation (LTP. We have extended this line of research to show that bidirectional plasticity is affected in the opposite way in rats expressing a dominant-negative mutant of NPR-B (NSE-NPR-BdeltaKC lacking the intracellular guanylyl cyclase domain under control of a promoter for neuron-specific enolase. The brain cells of these transgenic rats express functional dimers of the NPR-B receptor containing the dominant-negative NPR-BdeltaKC mutant, and therefore show decreased CNP-stimulated cGMP-production in brain membranes. The NPR-B transgenic rats display enhanced LTP but reduced LTD in hippocampal slices. When the frequency-dependence of synaptic modification to afferent stimulation in the range of 1-100 Hz was assessed in transgenic rats the threshold for LTP induction was raised, but LTD induction was facilitated. In parallel, NPR-BdeltaKC rats exhibited an enhancement in exploratory and learning behavior. These results indicate that bidirectional plasticity and learning and memory mechanism are affected in transgenic rats expressing a dominant-negative mutant of NPR-B. Our data substantiate the hypothesis that NPR-B-dependent cGMP signalling has a modulatory role for synaptic information storage and learning.

  16. Genetic deletion of melanin-concentrating hormone neurons impairs hippocampal short-term synaptic plasticity and hippocampal-dependent forms of short-term memory.

    Science.gov (United States)

    Le Barillier, Léa; Léger, Lucienne; Luppi, Pierre-Hervé; Fort, Patrice; Malleret, Gaël; Salin, Paul-Antoine

    2015-11-01

    The cognitive role of melanin-concentrating hormone (MCH) neurons, a neuronal population located in the mammalian postero-lateral hypothalamus sending projections to all cortical areas, remains poorly understood. Mainly activated during paradoxical sleep (PS), MCH neurons have been implicated in sleep regulation. The genetic deletion of the only known MCH receptor in rodent leads to an impairment of hippocampal dependent forms of memory and to an alteration of hippocampal long-term synaptic plasticity. By using MCH/ataxin3 mice, a genetic model characterized by a selective deletion of MCH neurons in the adult, we investigated the role of MCH neurons in hippocampal synaptic plasticity and hippocampal-dependent forms of memory. MCH/ataxin3 mice exhibited a deficit in the early part of both long-term potentiation and depression in the CA1 area of the hippocampus. Post-tetanic potentiation (PTP) was diminished while synaptic depression induced by repetitive stimulation was enhanced suggesting an alteration of pre-synaptic forms of short-term plasticity in these mice. Behaviorally, MCH/ataxin3 mice spent more time and showed a higher level of hesitation as compared to their controls in performing a short-term memory T-maze task, displayed retardation in acquiring a reference memory task in a Morris water maze, and showed a habituation deficit in an open field task. Deletion of MCH neurons could thus alter spatial short-term memory by impairing short-term plasticity in the hippocampus. Altogether, these findings could provide a cellular mechanism by which PS may facilitate memory encoding. Via MCH neuron activation, PS could prepare the day's learning by increasing and modulating short-term synaptic plasticity in the hippocampus.

  17. Biphasic euchromatin-to-heterochromatin transition on the KSHV genome following de novo infection.

    Directory of Open Access Journals (Sweden)

    Zsolt Toth

    Full Text Available The establishment of latency is an essential step for the life-long persistent infection and pathogenesis of Kaposi's sarcoma-associated herpesvirus (KSHV. While the KSHV genome is chromatin-free in the virions, the viral DNA in latently infected cells has a chromatin structure with activating and repressive histone modifications that promote latent gene expression but suppress lytic gene expression. Here, we report a comprehensive epigenetic study of the recruitment of chromatin regulatory factors onto the KSHV genome during the pre-latency phase of KSHV infection. This demonstrates that the KSHV genome undergoes a biphasic chromatinization following de novo infection. Initially, a transcriptionally active chromatin (euchromatin, characterized by high levels of the H3K4me3 and acetylated H3K27 (H3K27ac activating histone marks, was deposited on the viral episome and accompanied by the transient induction of a limited number of lytic genes. Interestingly, temporary expression of the RTA protein facilitated the increase of H3K4me3 and H3K27ac occupancy on the KSHV episome during de novo infection. Between 24-72 hours post-infection, as the levels of these activating histone marks declined on the KSHV genome, the levels of the repressive H3K27me3 and H2AK119ub histone marks increased concomitantly with the decline of lytic gene expression. Importantly, this transition to heterochromatin was dependent on both Polycomb Repressive Complex 1 and 2. In contrast, upon infection of human gingiva-derived epithelial cells, the KSHV genome underwent a transcription-active euchromatinization, resulting in efficient lytic gene expression. Our data demonstrate that the KSHV genome undergoes a temporally-ordered biphasic euchromatin-to-heterochromatin transition in endothelial cells, leading to latent infection, whereas KSHV preferentially adopts a transcriptionally active euchromatin in oral epithelial cells, resulting in lytic gene expression. Our results

  18. Electrochemical assessment of water|ionic liquid biphasic systems towards cesium extraction from nuclear waste

    Energy Technology Data Exchange (ETDEWEB)

    Stockmann, T. Jane [Laboratoire d’Electrochimie Physique et Analytique, Ecole Polytechnique Fédérale de Lausanne (EPFL), Station 6, Lausanne CH-1015 (Switzerland); Department of Chemistry, The University of Western Ontario, 1151 Richmond Street, London, Ontario N6A 5B7 (Canada); Zhang, Jing; Montgomery, Anne-Marie [Department of Chemistry, The University of Western Ontario, 1151 Richmond Street, London, Ontario N6A 5B7 (Canada); Ding, Zhifeng, E-mail: zfding@uwo.ca [Department of Chemistry, The University of Western Ontario, 1151 Richmond Street, London, Ontario N6A 5B7 (Canada)

    2014-04-01

    Highlights: • Electroanalytical chemistry was employed to assess cesium ion extraction in biphasic systems. • Water|ionic liquid systems are much more efficient than traditional water|organic ones. • The metal ion to ligand stoichiometry and overall complexation constant were determined. • The stoichiometry was confirmed by mass spectrometry. • The ligand CMPO used in TRUEX processes was found to be effective for the FIT. Abstract: A room temperature ionic liquid (IL) composed of a quaternary alkylphosphonium (trihexyltetradecylphosphonium, P66614⁺) and tetrakis(pentafluorophenyl)borate anion (TB⁻) was employed within a water|P66614TB (w|P66614TB or w|IL) biphasic system to evaluate cesium ion extraction in comparison to that with a traditional water|organic solvent (w|o) combination. ¹³⁷Cs is a major contributor to the radioactivity of spent nuclear fuel as it leaves the reactor, and its extraction efficiency is therefore of considerable importance. The extraction was facilitated by the ligand octyl(phenyl)-N,N'-diisobutylcarbamoylphosphine oxide (CMPO) used in TRans-Uranium EXtraction processes and investigated through well established liquid|liquid electrochemistry. This study gave access to the metal ion to ligand (1:n) stoichiometry and overall complexation constant, β, of the interfacial complexation reaction which were determined to be 1:3 and 1.6 × 10¹¹ at the w|P66614TB interface while the study at w|o elicited an n equal to 1 with β equal to 86.5. Through a straightforward relationship, these complexation constant values were converted to distribution coefficients, δα, with the ligand concentrations studied for comparison to other studies present in the literature; the w|o and w|IL systems gave δα of 2 and 8.2 × 10⁷, respectively, indicating a higher overall extraction efficiency for the latter. For the w|o system, the metal ion-ligand stoichiometries were

  19. Longitudinal testing of hippocampal plasticity reveals the onset and maintenance of endogenous human Aß-induced synaptic dysfunction in individual freely behaving pre-plaque transgenic rats: rapid reversal by anti-Aß agents.

    Science.gov (United States)

    Qi, Yingjie; Klyubin, Igor; Harney, Sarah C; Hu, NengWei; Cullen, William K; Grant, Marianne K; Steffen, Julia; Wilson, Edward N; Do Carmo, Sonia; Remy, Stefan; Fuhrmann, Martin; Ashe, Karen H; Cuello, A Claudio; Rowan, Michael J

    2014-12-24

    Long before synaptic loss occurs in Alzheimer's disease significant harbingers of disease may be detected at the functional level. Here we examined if synaptic long-term potentiation is selectively disrupted prior to extracellular deposition of Aß in a very complete model of Alzheimer's disease amyloidosis, the McGill-R-Thy1-APP transgenic rat. Longitudinal studies in freely behaving animals revealed an age-dependent, relatively rapid-onset and persistent inhibition of long-term potentiation without a change in baseline synaptic transmission in the CA1 area of the hippocampus. Thus the ability of a standard 200 Hz conditioning protocol to induce significant NMDA receptor-dependent short- and long-term potentiation was lost at about 3.5 months of age and this deficit persisted for at least another 2-3 months, when plaques start to appear. Consistent with in vitro evidence for a causal role of a selective reduction in NMDA receptor-mediated synaptic currents, the deficit in synaptic plasticity in vivo was associated with a reduction in the synaptic burst response to the conditioning stimulation and was overcome using stronger 400 Hz stimulation. Moreover, intracerebroventricular treatment for 3 days with an N-terminally directed monoclonal anti- human Aß antibody, McSA1, transiently reversed the impairment of synaptic plasticity. Similar brief treatment with the BACE1 inhibitor LY2886721 or the γ-secretase inhibitor MRK-560 was found to have a comparable short-lived ameliorative effect when tracked in individual rats. These findings provide strong evidence that endogenously generated human Aß selectively disrupts the induction of long-term potentiation in a manner that enables potential therapeutic options to be assessed longitudinally at the pre-plaque stage of Alzheimer's disease amyloidosis.

  20. Agrin and synaptic laminin are required to maintain adult neuromuscular junctions.

    Directory of Open Access Journals (Sweden)

    Melanie A Samuel

    Full Text Available As synapses form and mature the synaptic partners produce organizing molecules that regulate each other's differentiation and ensure precise apposition of pre- and post-synaptic specializations. At the skeletal neuromuscular junction (NMJ, these molecules include agrin, a nerve-derived organizer of postsynaptic differentiation, and synaptic laminins, muscle-derived organizers of presynaptic differentiation. Both become concentrated in the synaptic cleft as the NMJ develops and are retained in adulthood. Here, we used mutant mice to ask whether these organizers are also required for synaptic maintenance. Deletion of agrin from a subset of adult motor neurons resulted in the loss of acetylcholine receptors and other components of the postsynaptic apparatus and synaptic cleft. Nerve terminals also atrophied and eventually withdrew from muscle fibers. On the other hand, mice lacking the presynaptic organizer laminin-α4 retained most of the synaptic cleft components but exhibited synaptic alterations reminiscent of those observed in aged animals. Although we detected no marked decrease in laminin or agrin levels at aged NMJs, we observed alterations in the distribution and organization of these synaptic cleft components suggesting that such changes could contribute to age-related synaptic disassembly. Together, these results demonstrate that pre- and post-synaptic organizers actively function to maintain the structure and function of adult NMJs.