The physical distance between presynaptic Ca(2+) channels and the Ca(2+) sensors that trigger exocytosis of neurotransmitter-containing vesicles is a key determinant of the signalling properties of synapses in the nervous system. Recent functional analysis indicates that in some fast central synapses, transmitter release is triggered by a small number of Ca(2+) channels that are coupled to Ca(2+) sensors at the nanometre scale. Molecular analysis suggests that this tight coupling is generated by protein-protein interactions involving Ca(2+) channels, Ca(2+) sensors and various other synaptic proteins. Nanodomain coupling has several functional advantages, as it increases the efficacy, speed and energy efficiency of synaptic transmission.

SummaryLoss-of-function mutations in the synaptic adhesion protein Neuroligin-4 are among the most common genetic abnormalities associated with autism spectrum disorders, but little is known about the function of Neuroligin-4 and the consequences of its loss. We assessed synaptic and network characteristics in Neuroligin-4 knockout mice, focusing on the hippocampus as a model brain region with a critical role in cognition and memory, and found that Neuroligin-4 deletion causes subtle defects of the protein composition and function of GABAergic synapses in the hippocampal CA3 region. Interestingly, these subtle synaptic changes are accompanied by pronounced perturbations of γ-oscillatory network activity, which has been implicated in cognitive function and is altered in multiple psychiatric and neurodevelopmental disorders. Our data provide important insights into the mechanisms by which Neuroligin-4-dependent GABAergic synapses may contribute to autism phenotypes and indicate new strategies for therapeutic approaches.

Spontaneous postsynaptic currents (PSCs) provide key information about the mechanisms of synaptic transmission and the activity modes of neuronal networks. However, detecting spontaneous PSCs in vitro and in vivo has been challenging, because of the small amplitude, the variable kinetics, and the undefined time of generation of these events. Here, we describe a, to our knowledge, new method for detecting spontaneous synaptic events by deconvolution, using a template that approximates the average time course of spontaneous PSCs. A recorded PSC trace is deconvolved from the template, resulting in a series of delta-like functions. The maxima of these delta-like events are reliably detected, revealing the precise onset times of the spontaneous PSCs. Among all detection methods, the deconvolution-based method has a unique temporal resolution, allowing the detection of individual events in high-frequency bursts. Furthermore, the deconvolution-based method has a high amplitude resolution, because deconvolution can substantially increase the signal/noise ratio. When tested against previously published methods using experimental data, the deconvolution-based method was superior for spontaneous PSCs recorded in vivo. Using the high-resolution deconvolution-based detection algorithm, we show that the frequency of spontaneous excitatory postsynaptic currents in dentate gyrus granule cells is 4.5 times higher in vivo than in vitro.

The coupling between presynaptic Ca 2ϩ channels and Ca 2ϩ sensors of exocytosis is a key determinant of synaptic transmission. Evoked release from parvalbumin (PV)-expressing interneurons is triggered by nanodomain coupling of P/Q-type Ca 2ϩ channels, whereas release from cholecystokinin (CCK)-containing interneurons is generated by microdomain coupling of N-type channels. Nanodomain coupling has several functional advantages, including speed and efficacy of transmission. One potential disadvantage is that stochastic opening of presynaptic Ca 2ϩ channels may trigger spontaneous transmitter release. We addressed this possibility in rat hippocampal granule cells, which receive converging inputs from different inhibitory sources. Both reduction of extracellular Ca 2ϩ concentration and the unselective Ca 2ϩ channel blocker Cd 2ϩ reduced the frequency of miniature IPSCs (mIPSCs) in granule cells by ϳ50%, suggesting that the opening of presynaptic Ca 2ϩ channels contributes to spontaneous release. Application of the selective P/Q-type Ca 2ϩ channel blocker -agatoxin IVa had no detectable effects, whereas both the N-type blocker -conotoxin GVIa and the L-type blocker nimodipine reduced mIPSC frequency. Furthermore, both the fast Ca 2ϩ chelator BAPTA-AM and the slow chelator EGTA-AM reduced the mIPSC frequency, suggesting that Ca 2ϩ -dependent spontaneous release is triggered by microdomain rather than nanodomain coupling. The CB 1 receptor agonist WIN 55212-2 also decreased spontaneous release; this effect was occluded by prior application of -conotoxin GVIa, suggesting that a major fraction of Ca 2ϩ -dependent spontaneous release was generated at the terminals of CCK-expressing interneurons. Tonic inhibition generated by spontaneous opening of presynaptic N-and L-type Ca 2ϩ channels may be important for hippocampal information processing.