Presynaptic Muscarinic Receptors Reduce Synaptic Depression and Facilitate its Recovery at Hippocampal GABAergic Synapses

Hippocampal gamma oscillation, involved in cognitive processes, can be induced by muscarinic acetylcholine receptors activation and depends in large part on the activation of gamma-aminobutyric acidergic (GABAergic) interneurons. The precise role of the modulatory action of muscarinic receptors on GABAergic transmission still remains unclear due to the great heterogeneity of observed effects. We have examined the presynaptic and postsynaptic mechanisms involved. Methacholine induces a down-regulation of evoked inhibitory postsynaptic currents (eIPSCs) not associated with the change of postsynaptic receptors. The significant decrease in the paired-pulse depression strongly suggested a presynaptic mechanism of action. We have used cumulative amplitude profile analysis to show that the impairment of eIPSCs is not related to a decreased size of the readily releasable pool, but rather depends on the reduced release probability by a down-modulation of voltage-gated calcium channels. The decreased neurotransmitter release probability only partially accounts for the dramatic reduction in the rate of synaptic depression evoked by short- and long-lasting tetanic stimuli. This effect is accompanied by a significant enhancement in the rate of recovery from synaptic depression that demonstrates the reinforcement of the synaptic recycling processes. These results show that muscarinic modulation of hippocampal GABAergic synapses confers a greater resistance to sustain periods of intense synaptic activity in the gamma frequency range.