G-PROTEIN-COUPLED RECEPTORS MEDIATE A FAST EXCITATORY POSTSYNAPTIC CURRENT IN CA3 PYRAMIDAL NEURONS IN HIPPOCAMPAL SLICES

Synaptic activation in the presence of competitive (D,L-APV, CNQX) and noncompetitive (MK-801, GYKI-52466) ionotropic glutamate receptor ant agonists induced fast (10-90% rise time of 15-30 msec) postsynaptic re sponses in CA3 pyramidal neurons from acute and cultured hippocampal s lices. Postsynaptic currents were studied extensively in slice culture s, and displayed a linear current-voltage relationship, with a reversa l potential between 0 mV and +10 mV, suggesting the activation of a no nselective cationic conductance. Inhibition of the GTPase cycle by int racellular perfusion with the nonhydrolyzable analog of GDP, GDP beta S, blocked the fast postsynaptic responses evoked in ionotropic antago nists, as well as baclofen-mediated outward K+ currents, known to be m ediated by G protein-coupled GABA(B) receptors. Intracellular perfusio n with GDP beta S did not affect the AMPA/kainate component of the syn aptic currents. Irreversible activation of G proteins by intracellular perfusion with the nonhydrolyzable analog of GTP, GMP-PNP, occluded t he baclofen responses, and evoked an inward current, consistent with t he synaptically mediated conductance. Incubation of the slice cultures in pertussis toxin for 72 hr blocked baclofen-induced outward K+ curr ents, while the fast postsynaptic currents remained. The metabotropic glutamate receptor (mGluR) agonists 1S,3R-ACPD and 1S,3S-ACPD induced an inward current in the presence of the ionotropic antagonists, and o ccluded the fast EPSCs. The fast EPSCs were partially blocked by the m GluR antagonists L-AP3 and (+)MCPG, but there was differential antagon ist sensitivity in two pathways stimulated (CA3 stratum radiatum vs CA 3 stratum oriens). These data suggest that fast postsynaptic responses evoked in the presence of ionotropic glutamate receptor antagonists a re mediated by G protein-coupled mGluRs linked to nonselective cationi c channels.