Most neuronal networks, even in the absence of external stimuli, produce spontaneous bursts of spikes separated by periods of reduced activity. The origin and functional role of these neuronal events are still unclear. The present work shows that the spontaneous activity of two very different networks, intact leech ganglia and dissociated cultures of rat hippocampal neurons, share several features. Indeed, in both networks: i) the inter-spike intervals distribution of the spontaneous firing of single neurons is either regular or periodic or bursting, with the fraction of bursting neurons depending on the network activity; ii) bursts of spontaneous spikes have the same broad distributions of size and duration; iii) the degree of correlated activity increases with the bin width, and the power spectrum of the network firing rate has a 1/f behavior at low frequencies, indicating the existence of long-range temporal correlations; iv) the activity of excitatory synaptic pathways mediated by NMDA receptors is necessary for the onset of the long-range correlations and for the presence of large bursts; v) blockage of inhibitory synaptic pathways mediated by GABAA receptors causes instead an increase in the correlation among neurons and leads to a burst distribution composed only of very small and very large bursts. These results suggest that the spontaneous electrical activity in neuronal networks with different architectures and functions can have very similar properties and common dynamics.

At least two rate-limiting mechanisms in vesicle trafficking operate at mouse Schaffer collateral synapses, but their molecular/physical identities are unknown. The first mechanism determines the baseline rate at which reserve vesicles are supplied to a readily releasable pool. The second causes the supply rate to depress threefold when synaptic transmission is driven hard for extended periods. Previous models invoked depletion of a reserve vesicle pool to explain the reductions in the supply rate, but the mass-action assumption at their core is not compatible with kinetic measurements of neurotransmission under maximal-use conditions. Here we develop a new theoretical model of rate-limiting steps in vesicle trafficking that is compatible with previous and new measurements. A physical interpretation is proposed where local reserve pools consisting of four vesicles are tethered to individual release sites and are replenished stochastically in an all-or-none fashion. We then show that the supply rate depresses more rapidly in synapsin knock-outs and that the phenotype can be fully explained by changing the value of the single parameter in the model that would specify the size of the local reserve pools. Vesicle-trafficking rates between pools were not affected. Finally, optical imaging experiments argue against alternative interpretations of the theoretical model where vesicle trafficking is inhibited without reserve pool depletion. This new conceptual framework will be useful for distinguishing which of the multiple molecular and cell biological mechanisms involved in vesicle trafficking are rate limiting at different levels of synaptic throughput and are thus candidates for physiological and pharmacological modulation.

Short-term plasticity occurs at most central chemical synapses and includes both positive and negative components, but the principles governing interaction between components are largely unknown. The residual Ca(2+) that persists in presynaptic terminals for several seconds after repetitive use is known to enhance neurotransmitter release under artificial, low probability of release conditions where depression is absent; this is termed augmentation. However, the full impact of augmentation under standard conditions at synapses where depression dominates is not known because of possibly complicated convolution with a variety of potential depression mechanisms. This report shows that residual Ca(2+) continues to have a large enhancing impact on release at excitatory hippocampal synapses recovering from depression, including when only recently recruited vesicles are available for release. No evidence was found for gradual vesicle priming or for fast refilling of a highly releasable subdivision of the readily releasable pool (RRP). And decay of enhancement matched the clearance of residual Ca(2+), thus matching the behavior of augmentation when studied in isolation. Because of incomplete RRP replenishment, synaptic strength was not typically increased above baseline when residual Ca(2+) levels were highest. Instead residual Ca(2+) caused single pulse release probability to rebound quickly from depression and then depress quickly during subsequent bursts of activity. Together, these observations can help resolve discrepancies in recent timing estimates of recovery from depression. Additionally, in contrast to results obtained under reduced release conditions, augmentation could be driven to a maximal level, occluding paired-pulse facilitation and other mechanisms that increase release efficiency.

Garcia-Perez E, Lo DC, Wesseling JF. Kinetic isolation of a slowly recovering component of short-term depression during exhaustive use at excitatory hippocampal synapses. J Neurophysiol 100: 781-795, 2008. First published June 25, 2008 doi:10.1152/jn.90429.2008. This study examines the kinetics of the longest lasting form of short-term depression at excitatory hippocampal synapses. After initial depletion of the readily releasable pool (RRP), continued 20-Hz stimulation was found to be fast enough to maximally drive presynaptic neurotransmitter exocytosis; maximal is defined here as the rate needed to maintain the RRP in a nearly empty steady state. Induction of depression proceeded in two distinct phases. The first was caused by RRP depletion, whereas the second is shown to reflect the progressive reduction of the overall rate at which new vesicles are supplied to the RRP and is termed "supply-rate depression." Supply-rate depression is identified further with the emergence, during heavy use, of a rate-limiting vesicle trafficking step that slows the timing of RRP replenishment by switching from a fast ( Х 7 s) to a slow ( Х 1 min) vesicle supply mechanism. Both mechanisms apparently follow firstorder kinetics. After the induction of the maximum amount of depression, individual synapses were able to output only Ͻ1 quantum of neurotransmitter per synapse per second, matching previous predictions based on cell biological measurements of synaptic vesicle cycling. Surprisingly, the onset of supply-rate depression occurred with a marked delay, not having a detectable impact on synaptic function until after several seconds of continuous use. The delayed onset is not consistent with traditional vesicle trafficking models, but may be important for limiting the impact of supply-rate depression to pathological episodes and might function as a native antiepilepsy device.

Interactions among chemical and electrical synapses regulate the patterns of electrical activity of vertebrate and invertebrate neurons. In this investigation we studied how electrical coupling influences the integration of excitatory postsynaptic potentials (EPSPs). Pairs of Retzius neurons of the leech are coupled by a nonrectifying electrical synapse by which chemically induced synaptic currents flow from one neuron to the other. Results from electrophysiology and modeling suggest that chemical synaptic inputs are located on the coupled neurites, at 7.5 microm from the electrical synapses. We also showed that the space constant of the coupled neurites was 100 microm, approximately twice their length, allowing the efficient spread of synaptic currents all along both coupled neurites. Based on this cytoarchitecture, our main finding was that the degree of electrical coupling modulates the amplitude of EPSPs in the driving neurite by regulating the leak of synaptic current to the coupled neurite, so that the amplitude of EPSPs in the driving neurite was proportional to the value of the coupling resistance. In contrast, synaptic currents arriving at the coupled neurite through the electrical synapse produced EPSPs of constant amplitude. This was because the coupling resistance value had inverse effects on the amount of current arriving and on the impedance of the neurite. We propose that by modulating the amplitude of EPSPs, electrical synapses could regulate the firing frequency of neurons.