A CYCLIC-AMP-DEPENDENT FORM OF ASSOCIATIVE SYNAPTIC PLASTICITY INDUCED BY COACTIVATION OF BETA-ADRENERGIC RECEPTORS AND METABOTROPIC GLUTAMATE RECEPTORS IN RAT HIPPOCAMPUS

Recent studies suggest that increases in intracellular cAMP increase e voked synaptic responses in area CA1 of the hippocampus. We recently r eported that activation of metabotropic glutamate receptors (mGluRs) i n hippocampal slices potentiates cAMP responses to activation of other receptors that are positively coupled to adenylyl cyclase through Gs. It is possible that by enhancing cAMP responses, mGluRs could markedl y potentiate the ability of agonists of Gs-coupled receptors to potent iate synaptic responses in area CA1. Such synergistic activation of a second messenger system could be involved in an associative form of ne uronal plasticity in which simultaneous activation of two independent inputs to a cell is required for induction of a given change in synapt ic transmission or neuronal excitability. We therefore tested the hypo thesis that coactivation of mGluRs and a Gs-coupled receptor (the beta -adrenergic receptor) could lead to large increases in cAMP accumulati on in hippocampus and thereby increase synaptic responses in area CA1. We report that coactivation of mGluRs and beta-adrenergic receptors l eads to a lasting (> 30 min) increase in the amplitude of evoked popul ation spikes at the Schaffer collateral-CA1 synapse. This effect is no t accompanied by an increase in excitatory postsynaptic currents or by a decrease in synaptic inhibition in area CA1, suggesting that it is not mediated by a lasting change in excitatory or inhibitory synaptic transmission. However, coactivation of these receptors leads to a pers istent depolarization of CA1 pyramidal cells with a concomitant increa se in input resistance. Furthermore, coactivation of these receptors i nduces a lasting decrease in a slow afterhyperpolarization that follow s a burst of action potentials in these cells and a lasting decrease i n spike frequency adaptation. These electrophysiological effects are b locked by the protein kinase inhibitor staurosporine. Biochemical data suggest that the persistent increase in excitability of these cells i s not mediated by a lasting increase in cAMP production. Taken togethe r with previous reports demonstrating that cAMP analogs and the adenyl yl cyclase activator forskolin mimic these effects, these data suggest that the response to coactivation of mGluRs and beta-adrenergic recep tors is mediated by formation of cAMP and activation of cAMP-dependent protein kinase. This may represent a novel mechanism for an associati ve form of synaptic plasticity in the mammalian brain.