Role of muscarinic receptors, G‐proteins, and intracellular messengers in muscarinic modulation of NMDA receptor‐mediated synaptic transmission

Previously, we reported that activation of muscarinic receptors modulates N‐methyl‐D‐aspartate (NMDA) receptor‐mediated synaptic transmission in auditory neocortex [Aramakis et al. (1997a) Exp Brain Res 113:484–496]. Here, we describe the muscarinic subtypes responsible for these modulatory effects, and a role for G‐proteins and intracellular messengers. The muscarinic agonist oxotremorine‐M (oxo‐M), at 25–100 μM, produced a long‐lasting enhancement of NMDA‐induced membrane depolarizations. We examined the postsynaptic G‐protein dependence of the modulatory effects of oxo‐M with the use of the G‐protein activator GTPγS and the nonhydrolyzable GDP analog GDPβS. Intracellular infusion of GTPγS mimicked the facilitating actions of oxo‐M. After obtaining the whole‐cell recording configuration, there was a gradual, time‐dependent increase of the NMDA receptor‐mediated slow‐EPSP, and of iontophoretic NMDA‐induced membrane depolarizations. In contrast, intracellular infusion of either GDPβS or the IP 3 receptor antagonist heparin prevented oxo‐M mediated enhancement of NMDA depolarizations. The muscarinic receptor involved in enhancement of NMDA iontophoretic responses is likely the M 1 receptor, because the increase was prevented by pirenzepine, but not the M 2 antagonists methoctramine or AF‐DX 116. Oxo‐M also reduced the amplitude of the pharmacologically isolated slow‐EPSP, and this effect was blocked by M 2 antagonists. Thus, muscarinic‐mediated enhancement of NMDA responses involves activation of M 1 receptors, leading to the engagement of a postsynaptic G‐protein and subsequent IP 3 receptor activity. Synapse 32:262–275, 1999. © 1999 Wiley‐Liss, Inc.