Two distinct mechanisms of muscarinic receptor-mediated suppression of hippocampal inhibitory synapses

Abstract

Muscarinic acetylcholine receptors are believed to play important roles in higher brain functions. Here we report that muscarinic activation suppresses inhibitory transmission through two distinct mechanisms, namely cannabinoid-dependent and -independent mechanisms. When cannabinoid CB1 receptor was blocked, oxotremorine M (oxo-M), a muscarinic agonist, suppressed IPSCs in a subset of hippocampal neuron pairs. This suppression was blocked by the M2-prefering antagonist gallamine, and totally absent in neuron pairs from M2-KO mice. When CB1 was not blocked, oxo-M suppressed IPSCs in a gallamine-resistant manner in cannabinoid-sensitive pairs. This suppression was blocked by the CB1 antagonist AM281, and completely eliminated in neuron pairs from M1/M3-KO mice. Our immunohistochemical examination showed that M2 and CB1 were present at different inhibitory presynaptic terminals. These results indicate that two distinct mechanisms mediate the muscarinic suppression. In a subset of synapses, activation of presynaptic M2 suppresses GABA release directly. In contrast, in a different subset of synapses, activation of postsynaptic M1/M3 induces the release of endocannabinoids that act on presynaptic CB1 receptors and suppress the GABA release. [Jpn J Physiol 54 Suppl:S150 (2004)]