Properties of synaptic transmission at single hippocampal synaptic boutons.
ABSTRACT Synaptic transmission between individual presynaptic terminals and postsynaptic dendrites is a fundamental element of communication among central nervous system neurons. Yet little is known about evoked neurotransmission at the level of single presynaptic boutons. Here we describe key functional characteristics of individual presynaptic boutons of hippocampal neurons in culture. Excitatory postsynaptic currents (e.p.s.cs) were evoked by localized application of elevated K+/Ca2+ solution to single functional boutons, visually identified by staining with the vital dye FM1-43 (refs 6, 7). Frequent repetitive stimulation produced a decline in the incidence of e.p.s.cs as the pool of releasable vesicles was exhausted; typically, recovery proceeded with a time constant of about 40 s (23 degrees C), and involved a vesicular pool capable of generating about 90 e.p.s.cs without recycling. At individual synapses, synaptic currents were broadly distributed in amplitude, but this distribution was remarkably similar at multiple synapses on a given postsynaptic neuron. The average size of synaptic currents and of responses to focal glutamate application varied fourfold across different cells, decreasing markedly with increasingly dense synaptic innervation. This raises the possibility of a very effective mechanism for coordinating synaptic strength at multiple sites throughout the dendritic tree.
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ABSTRACT: Reliable signal transmission constitutes a key requirement for neural circuit function. The propagation of synchronous pulse packets through recurrent circuits is hypothesized to be one robust form of signal transmission and has been extensively studied in computational and theoretical works. Yet, although external or internally generated oscillations are ubiquitous across neural systems, their influence on such signal propagation is unclear. Here we systematically investigate the impact of oscillations on propagating synchrony. We find that for standard, additive couplings and a net excitatory effect of oscillations, robust propagation of synchrony is enabled in less prominent feed-forward structures than in systems without oscillations. In the presence of non-additive coupling (as mediated by fast dendritic spikes), even balanced oscillatory inputs may enable robust propagation. Here, emerging resonances create complex locking patterns between oscillations and spike synchrony. Interestingly, these resonances make the circuits capable of selecting specific pathways for signal transmission. Oscillations may thus promote reliable transmission and, in co-action with dendritic nonlinearities, provide a mechanism for information processing by selectively gating and routing of signals. Our results are of particular interest for the interpretation of sharp wave/ripple complexes in the hippocampus, where previously learned spike patterns are replayed in conjunction with global high-frequency oscillations. We suggest that the oscillations may serve to stabilize the replay.PLoS Computational Biology 12/2014; 10(12):e1003940. · 4.87 Impact Factor
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ABSTRACT: Objective To determine if levetiracetam (LEV) enhances the impact in excitatory presynaptic terminals of a rate-limiting mechanism in vesicle trafficking termed supply rate depression that emerges to limit synaptic transmission during heavy, epileptiform use.Methods The effect of LEV was measured with electrophysiologic assays of monosynaptic connections in ex vivo hippocampal slices from wild-type and synapsin knockout mice, and in primary cell culture neurons from wild-type and synaptic vesicle glycoprotein 2a (SV2a) knockout mice.ResultsLEV enhanced the impact of supply rate depression at Schaffer collateral synapses by shortening the time course for induction. The LEV effect was selective for supply rate depression because other presynaptic vesicle trafficking mechanisms were not affected. The half maximal effective concentration (EC50) was ~50 μm. The maximal effect was ~15 % and occurred at 100 μm, which is a clinically relevant concentration. An experimental protocol is established for distinguishing atypical antiepileptic drugs (AEDs) that affect supply rate depression, such as LEV, from typical AEDs, such as carbamazepine, that affect upstream mechanisms. The LEV effect was abolished at synapses from knockout mice lacking SV2a and from synapses lacking synapsin 1 and 2.SignificanceThe findings are consistent with the new hypothesis that LEV acts to treat epilepsy by accelerating the induction of supply rate depression at excitatory synapses during incipient epileptic activity. The absence of the effect in the knockouts confirms that presynaptic function is the target. More specifically, the absence in SV2a knockouts is consistent with previous binding studies suggesting that SV2a is the target for LEV. The absence in synapsin knockouts indicates that the phenotypic target intersects with the biochemical pathway that is altered in synapsin knockouts. The results from synapsin knockouts additionally suggest that development of functional analogs with increased potency might be possible because induction of supply rate depression is faster in synapsin knockouts compared to wild-type synapses treated with LEV.Epilepsia 02/2015; · 4.58 Impact Factor
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ABSTRACT: The complex manner in which patterns of presynaptic neural activity are translated into short-term plasticity (STP) suggests the existence of multiple presynaptic calcium (Ca(2+)) sensors, which regulate the amplitude and time-course of STP and are the focus of this review. We describe two canonical Ca(2+)-binding protein domains (C2 domains and EF-hands) and define criteria that need to be met for a protein to qualify as a Ca(2+) sensor mediating STP. With these criteria in mind, we discuss various forms of STP and identify established and putative Ca(2+) sensors. We find that despite the multitude of proposed sensors, only three are well established in STP: Munc13, protein kinase C (PKC) and synaptotagmin-7. For putative sensors, we pinpoint open questions and potential pitfalls. Finally, we discuss how the molecular properties and modes of action of Ca(2+) sensors can explain their differential involvement in STP and shape net synaptic output.Frontiers in Cellular Neuroscience 10/2014; 8:356. · 4.18 Impact Factor