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Neurotransmitter transporters may promote synapse specificity by limiting spillover between release sites. At GABAergic synapses, transport block prolongs synaptic responses when many inputs are activated, yet it is unclear whether transporters alter signaling by single axons. We found that unitary IPSCs generated by paired recordings between hippocampal interneurons and granule cells could be either prolonged or totally unaffected by block of GABA transporters. This variability was explained by the density of active release sites rather than the number of active sites. Prolongation by transport block required release from multiple sites and was enhanced by repetitive activation. Furthermore, transport-sensitive unitary IPSCs were accelerated when the release probability was reduced, indicating that cross talk prolonged the time course of IPSCs even when transport was intact. Our results suggest that the release site density regulates the degree of cross talk as well as the contribution of transporters to GABA clearance. Thus, interplay between release site density and transporter action determines the independence of unitary inhibitory synapses.

GABAergic inhibition, a primary target for pharmacological modulation of excitability in the CNS, can be altered by multiple mechanisms including alteration of GABA metabolism. Gamma-vinyl GABA (vigabatrin, GVG) is an irreversible inhibitor of the GABA catabolic enzyme GABA transaminase, thus its anticonvulsant properties are thought to result from an elevation of brain GABA levels. We examined the effects of GVG on GABAergic synaptic transmission in hippocampal slices. GVG unexpectedly reduced miniature and evoked inhibitory postsynaptic currents (IPSCs) in dentate granule cells. The reduction in synaptic events was accompanied by an increase in tonic GABA(A) receptor-mediated current. These effects developed slowly and persisted following wash out of GVG. The GVG pretreatment reduced sucrose-evoked GABA release as well as postsynaptic sensitivity to exogenous GABA, indicating that both pre- and postsynaptic mechanisms contributed to the reduction in synaptic currents. These results suggest that tonic rather than phasic increases in GABA underlie the anticonvulsant properties of GVG, and that mechanisms that elevate brain neurotransmitter levels do not necessarily correlate with enhanced synaptic release.

At central synapses, a large and fast spike of neurotransmitter efficiently activates postsynaptic receptors. However, low concentrations of transmitter can escape the cleft and activate presynaptic and postsynaptic receptors. We report here that low concentrations of GABA reduce IPSCs in hippocampal neurons by preferentially desensitizing rather than opening GABA(A) channels. GABA transporter blockade also caused desensitization by locally elevating GABA to approximately 1 microm. Recovery of the IPSC required several seconds, mimicking recovery of the channel from slow desensitization. These results indicate that low levels of GABA can regulate the amplitude of IPSCs by producing a slow form of receptor desensitization. Accumulation of channels in this absorbing state allows GABA(A) receptors to detect even a few molecules of GABA in the synaptic cleft.