Activity-dependent depression of GABAergic IPSCs in cultured hippocampal neurons

Short term depression of monosynaptic GABAergic inhibitory postsynaptic cur rents (IPSCs) evoked between pairs of cultured rat hippocampal neurons was investigated using dual whole cell patch-clamp recordings. Paired stimuli a pplied to the GABAergic neuron resulted in paired-pulse depression (PPD) of the second IPSC (IPSC2) at interpulse intervals from 25 to 2,000 ms. CGP 5 5845A, but not CGP 35348, reduced PPD marginally. Brief paired-pulse applic ations of exogenous GABA indicated that postsynaptic factors made only mini mal contribution to PPD of IPSCs. IPSC, and PPD was reduced on lowering [Ca 2+](o) and enhanced on increasing [Ca2+](o). The potassium-channel blocker 4-aminopyridine (4-AP), which increases presynaptic Ca2+ influx, enhanced I PSCI and PPD. Chelation of residual Ca2+ in the GABAergic boutons with EGTA -AM enhanced PPD. Stimulation of the presynaptic neuron at frequencies (f) ranging from 2.5 to 80 Hz resulted in tetanic depression of IPSCs, which de clined rapidly and reached a plateau depending on f and [Ca2+](o). CGP 5584 5A decreased tetanic depression in the first part of the train, but this co uld be overcome with continued stimulation. We show that GABAergic IPSCs ar e robustly depressed by paired-pulse stimulation in cultured hippocampal ne urons. The depression of IPSCs is mainly independent of presynaptic GABA(B) receptors and could be caused by depletion of releasable vesicles. Deplete d synapses recover with a slow time course, depending on factors that regul ate [Ca2+](i) in the GABAergic boutons.