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Modelling Vesicular Release at Hippocampal Synapses  [PDF]
Suhita Nadkarni ,Thomas M. Bartol ,Terrence J. Sejnowski ,Herbert Levine
PLOS Computational Biology , 2010, DOI: 10.1371/journal.pcbi.1000983
Abstract: We study local calcium dynamics leading to a vesicle fusion in a stochastic, and spatially explicit, biophysical model of the CA3-CA1 presynaptic bouton. The kinetic model for vesicle release has two calcium sensors, a sensor for fast synchronous release that lasts a few tens of milliseconds and a separate sensor for slow asynchronous release that lasts a few hundred milliseconds. A wide range of data can be accounted for consistently only when a refractory period lasting a few milliseconds between releases is included. The inclusion of a second sensor for asynchronous release with a slow unbinding site, and thereby a long memory, affects short-term plasticity by facilitating release. Our simulations also reveal a third time scale of vesicle release that is correlated with the stimulus and is distinct from the fast and the slow releases. In these detailed Monte Carlo simulations all three time scales of vesicle release are insensitive to the spatial details of the synaptic ultrastructure. Furthermore, our simulations allow us to identify features of synaptic transmission that are universal and those that are modulated by structure.
Spatial and Temporal Correlates of Vesicular Release at Hippocampal Synapses  [PDF]
Suhita Nadkarni,Thomas Bartol,Terrence Sejnowski,Herbert Levine
Quantitative Biology , 2010,
Abstract: We develop a spatially explicit biophysical model of the hippocampal CA3-CA1 presynaptic bouton to study local calcium dynamics leading to vesicle fusion. A kinetic model with two calcium sensors is formulated specifically for the CA3-CA1 synapse. The model includes a sensor for fast synchronous release that lasts a few tens of milliseconds and a sensor for slow asynchronous release that lasts a few hundred milliseconds. We show that a variety of extant data on CA3-CA1 synapse can be accounted for consistently only when a refractory period of the order of few milliseconds between releases is introduced. Including a second sensor for asynchronous release that has a slow unbinding site and therefore an embedded long memory, is shown to play a role in short-term plasticity by facilitating release. For synchronous release mediated by Synaptotagmin II a third time scale is revealed in addition to the fast and slow release. This third time scale corresponds to "stimulus-correlated super-fast" neurotransmitter release. Our detailed spatial simulation indicates that all three-time scales of neurotransmitter release are an emergent property of the calcium sensor and independent of synaptic ultrastructure. Furthermore, it allows us to identify features of synaptic transmission that are universal and those that are modulated by structure.
Inhibition of AMPA receptor trafficking at hippocampal synapses by β-amyloid oligomers: the mitochondrial contribution
Yanfang Rui, Jiaping Gu, Kuai Yu, H Criss Hartzell, James Q Zheng
Molecular Brain , 2010, DOI: 10.1186/1756-6606-3-10
Abstract: We found that a brief exposure of hippocampal neurons to Aβ oligomers not only led to marked removal of AMPARs from postsynaptic surface but also impaired rapid AMPAR insertion during chemically-induced synaptic potentiation. We also found that Aβ oligomers exerted acute impairment of fast mitochondrial transport, as well as mitochondrial translocation into dendritic spines in response to repetitive membrane depolarization. Quantitative analyses at the single spine level showed a positive correlation between spine-mitochondria association and the surface accumulation of AMPARs. In particular, we found that spines associated with mitochondria tended to be more resistant to Aβ inhibition on AMPAR trafficking. Finally, we showed that inhibition of GSK3β alleviated Aβ impairment of mitochondrial transport, and effectively abolished Aβ-induced AMPAR loss and inhibition of AMPAR insertion at spines during cLTP.Our findings indicate that mitochondrial association with dendritic spines may play an important role in supporting AMPAR presence on or trafficking to the postsynaptic membrane. Aβ disruption of mitochondrial trafficking could contribute to AMPAR removal and trafficking defects leading to synaptic inhibition.Alzheimer's disease (AD) often attacks aged populations and is highlighted by progressive loss of memory and cognitive abilities [4]. AD brains exhibit two major pathological hallmarks: extracellular senile plaques containing β-amyloid aggregates and intracellular neurofibrillary tangles consisting of hyperphosphorylated microtubule-associated tau proteins [5,6]. β-amyloid (Aβ) molecules are generated by proteolytic cleavage of the transmembrane β-amyloid precursor protein (APP) [7,8]. Aggregated Aβ fibrils constitute the core of neuritic plaques and are believed to be a major culprit for neurodegeneration and subsequent cognitive abnormalities in AD patients [9-11]. Recent studies, however, indicate that Aβ molecules exert adverse effects on neuronal functions
Loss of AP-3 function affects spontaneous and evoked release at hippocampal mossy fiber synapses  [PDF]
Anita Scheuber,Rachel Rudge,Lydia Danglot,Graca Raposo,Thomas Binz,Jean-Christophe Poncer,Thierry Galli
Quantitative Biology , 2006, DOI: 10.1073/pnas.0603511103
Abstract: Synaptic vesicle (SV) exocytosis mediating neurotransmitter release occurs spontaneously at low intraterminal calcium concentrations and is stimulated by a rise in intracellular calcium. Exocytosis is compensated for by the reformation of vesicles at plasma membrane and endosomes. Although the adaptor complex AP-3 was proposed to be involved in the formation of SVs from endosomes, whether its function has an indirect effect on exocytosis remains unknown. Using mocha mice, which are deficient in functional AP-3, we identify an AP-3-dependent tetanus neurotoxin-resistant asynchronous release that can be evoked at hippocampal mossy fiber (MF) synapses. Presynaptic targeting of the tetanus neurotoxin-resistant vesicle soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) tetanus neurotoxin-insensitive vesicle-associated membrane protein (TI-VAMP) is lost in mocha hippocampal MF terminals, whereas the localization of synaptobrevin 2 is unaffected. In addition, quantal release in mocha cultures is more frequent and more sensitive to sucrose. We conclude that lack of AP-3 results in more constitutive secretion and loss of an asynchronous evoked release component, suggesting an important function of AP-3 in regulating SV exocytosis at MF terminals.
MicroRNA132 Modulates Short-Term Synaptic Plasticity but Not Basal Release Probability in Hippocampal Neurons  [PDF]
Talley J. Lambert,Daniel R. Storm,Jane M. Sullivan
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0015182
Abstract: MicroRNAs play important regulatory roles in a broad range of cellular processes including neuronal morphology and long-term synaptic plasticity. MicroRNA-132 (miR132) is a CREB-regulated miRNA that is induced by neuronal activity and neurotrophins, and plays a role in regulating neuronal morphology and cellular excitability. Little is known about the effects of miR132 expression on synaptic function. Here we show that overexpression of miR132 increases the paired-pulse ratio and decreases synaptic depression in cultured mouse hippocampal neurons without affecting the initial probability of neurotransmitter release, the calcium sensitivity of release, the amplitude of excitatory postsynaptic currents or the size of the readily releasable pool of synaptic vesicles. These findings are the first to demonstrate that microRNAs can regulate short-term plasticity in neurons.
Astrocyte-mediated short-term synaptic depression in the rat hippocampal CA1 area: two modes of decreasing release probability
My S Andersson, Eric Hanse
BMC Neuroscience , 2011, DOI: 10.1186/1471-2202-12-87
Abstract: When tested using paired-pulses, following a period of inactivity, the transient heterosynaptic depression was expressed as a reduction in the response to only the first pulse, whereas the response to the second pulse was unaffected. This selective depression of only the first response in a high-frequency burst was shared by the homosynaptic post-burst depression, but it was partially counteracted by augmentation at these recently active synapses. In addition, the expression of the homosynaptic post-burst depression included an astrocyte-mediated reduction of the pool of release-ready primed vesicles.Our results suggest that activated astrocytes depress the release probability via two different mechanisms; by depression of vesicular release probability only at inactive synapses and by imposing a delay in the recovery of the primed pool of vesicles following depletion. These mechanisms restrict the expression of the astrocyte-mediated depression to temporal windows that are typical for synaptic burst activity.The probability of release (Pr) is a fundamental property of synapses that is regulated by presynaptic activity (short-term synaptic plasticity) [1] and by modulatory transmitters acting on presynaptic receptors [2-4]. Pr at rest (after seconds of inactivity) varies substantially among synapses [5] and is determined by two independent factors. One is the number of vesicles primed for release and thus potentially available for release by a single action potential, the primed pool. The other is the probability of releasing one primed vesicle (Pves) [6,7]. Repeated activation at short intervals, resulting in residual elevated calcium in the presynaptic terminal between activations, will change Pves, rapidly deplete the primed pool, and prime new vesicles in a calcium-dependent manner [8]. During high-frequency activation Pr is rather determined by the rate at which new vesicles can become available for release [7,9]. Thus, factors determining Pr differ depending on
Estrogen protects neuronal cells from amyloid beta-induced apoptosis via regulation of mitochondrial proteins and function
Jon Nilsen, Shuhua Chen, Ronald W Irwin, Sean Iwamoto, Roberta Brinton
BMC Neuroscience , 2006, DOI: 10.1186/1471-2202-7-74
Abstract: In this study, we investigated the mechanism of 17β-estradiol-induced prevention of amyloid beta-induced apoptosis of rat hippocampal neuronal cultures. Estradiol treatment prior to amyloid beta exposure significantly reduced the number of apoptotic neurons and the associated rise in resting intracellular calcium levels. Amyloid beta exposure provoked down regulation of a key antiapoptotic protein, Bcl-2, and resulted in mitochondrial translocation of Bax, a protein known to promote cell death, and subsequent release of cytochrome c. E2 pretreatment inhibited the amyloid beta-induced decrease in Bcl-2 expression, translocation of Bax to the mitochondria and subsequent release of cytochrome c. Further implicating the mitochondria as a target of estradiol action, in vivo estradiol treatment enhanced the respiratory function of whole brain mitochondria. In addition, estradiol pretreatment protected isolated mitochondria against calcium-induced loss of respiratory function.Therefore, we propose that estradiol pretreatment protects against amyloid beta neurotoxicity by limiting mitochondrial dysfunction via activation of antiapoptotic mechanisms.A growing body of evidence supports the critical role of amyloid beta peptide (Aβ)2 in Alzheimer's disease (AD) pathogenesis. Early onset AD is associated with overproduction of the 42-amino acid form of Aβ (Aβ1–42) and Aβ1–42 is toxic to neurons in vitro and in vivo [1-3]. To develop therapeutic strategies for reducing neuronal loss in AD, much effort has been extended to determine the molecular interactions underlying Aβ-induced neurotoxicity. Several lines of evidence suggest that calcium plays a key role in age-related changes in the brain that lead to AD and dementia [4-7]. Free intracellular calcium is a key activator of many signal transduction pathways of neurons, and alterations in intracellular calcium homeostasis are pivotal regulators of brain aging, memory and cell death [4-6,8-11]. According to a "calcium hypothesis
Independent Regulation of Basal Neurotransmitter Release Efficacy by Variable Ca2+ Influx and Bouton Size at Small Central Synapses  [PDF]
Yaroslav S. Ermolyuk,Felicity G. Alder,Christian Henneberger,Dmitri A. Rusakov,Dimitri M. Kullmann,Kirill E. Volynski
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.1001396
Abstract: The efficacy of action potential evoked neurotransmitter release varies widely even among synapses supplied by the same axon, and the number of release-ready vesicles at each synapse is a major determinant of this heterogeneity. Here we identify a second, equally important, mechanism for release heterogeneity at small hippocampal synapses, the inter-synaptic variation of the exocytosis probability of release-ready vesicles. Using concurrent measurements of vesicular pool sizes, vesicular exocytosis rates, and presynaptic Ca2+ dynamics, in the same small hippocampal boutons, we show that the average fusion probability of release-ready vesicles varies among synapses supplied by the same axon with the size of the spike-evoked Ca2+ concentration transient. We further show that synapses with a high vesicular release probability exhibit a lower Ca2+ cooperativity, arguing that this is a direct consequence of increased Ca2+ influx at the active zone. We conclude that variability of neurotransmitter release under basal conditions at small central synapses is accounted for not only by the number of release-ready vesicles, but also by their fusion probabilities, which are set independently of bouton size by variable spike-evoked presynaptic Ca2+ influx.
Independent Regulation of Basal Neurotransmitter Release Efficacy by Variable Ca2+ Influx and Bouton Size at Small Central Synapses  [PDF]
Yaroslav S. Ermolyuk,Felicity G. Alder,Christian Henneberger,Dmitri A. Rusakov,Dimitri M. Kullmann,Kirill E. Volynski
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.1001396
Abstract: The efficacy of action potential evoked neurotransmitter release varies widely even among synapses supplied by the same axon, and the number of release-ready vesicles at each synapse is a major determinant of this heterogeneity. Here we identify a second, equally important, mechanism for release heterogeneity at small hippocampal synapses, the inter-synaptic variation of the exocytosis probability of release-ready vesicles. Using concurrent measurements of vesicular pool sizes, vesicular exocytosis rates, and presynaptic Ca2+ dynamics, in the same small hippocampal boutons, we show that the average fusion probability of release-ready vesicles varies among synapses supplied by the same axon with the size of the spike-evoked Ca2+ concentration transient. We further show that synapses with a high vesicular release probability exhibit a lower Ca2+ cooperativity, arguing that this is a direct consequence of increased Ca2+ influx at the active zone. We conclude that variability of neurotransmitter release under basal conditions at small central synapses is accounted for not only by the number of release-ready vesicles, but also by their fusion probabilities, which are set independently of bouton size by variable spike-evoked presynaptic Ca2+ influx.
Dual Effect of Beta-Amyloid on α7 and α4β2 Nicotinic Receptors Controlling the Release of Glutamate, Aspartate and GABA in Rat Hippocampus  [PDF]
Elisa Mura, Stefania Zappettini, Stefania Preda, Fabrizio Biundo, Cristina Lanni, Massimo Grilli, Anna Cavallero, Guendalina Olivero, Alessia Salamone, Stefano Govoni, Mario Marchi
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0029661
Abstract: Background We previously showed that beta-amyloid (Aβ), a peptide considered as relevant to Alzheimer's Disease, is able to act as a neuromodulator affecting neurotransmitter release in absence of evident sign of neurotoxicity in two different rat brain areas. In this paper we focused on the hippocampus, a brain area which is sensitive to Alzheimer's Disease pathology, evaluating the effect of Aβ (at different concentrations) on the neurotransmitter release stimulated by the activation of pre-synaptic cholinergic nicotinic receptors (nAChRs, α4β2 and α7 subtypes). Particularly, we focused on some neurotransmitters that are usually involved in learning and memory: glutamate, aspartate and GABA. Methodology/Findings We used a dual approach: in vivo experiments (microdialysis technique on freely moving rats) in parallel to in vitro experiments (isolated nerve endings derived from rat hippocampus). Both in vivo and in vitro the administration of nicotine stimulated an overflow of aspartate, glutamate and GABA. This effect was greatly inhibited by the highest concentrations of Aβ considered (10 μM in vivo and 100 nM in vitro). In vivo administration of 100 nM Aβ (the lowest concentration considered) potentiated the GABA overflow evoked by nicotine. All these effects were specific for Aβ and for nicotinic secretory stimuli. The in vitro administration of either choline or 5-Iodo-A-85380 dihydrochloride (α7 and α4β2 nAChRs selective agonists, respectively) elicited the hippocampal release of aspartate, glutamate, and GABA. High Aβ concentrations (100 nM) inhibited the overflow of all three neurotransmitters evoked by both choline and 5-Iodo-A-85380 dihydrochloride. On the contrary, low Aβ concentrations (1 nM and 100 pM) selectively acted on α7 subtypes potentiating the choline-induced release of both aspartate and glutamate, but not the one of GABA. Conclusions/Significance The results reinforce the concept that Aβ has relevant neuromodulatory effects, which may span from facilitation to inhibition of stimulated release depending upon the concentration used.
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