Endogenous activation of nAChRs and NMDA receptors contributes to the excitability of CA1 stratum radiatum interneurons in rat hippocampal slices: Effects of kynurenic acid

CA1 stratum radiatum interneurons (SRIs) express alpha 7 nicotinic receptors (nAChRs) and receive inputs from glutamatergic neurons/axons that express alpha 3 beta 4 beta 2 nAChRs. To test the hypothesis that endogenously active alpha 7 and/or alpha 3 beta 4 beta 2 nAChRs control the excitability of CA1 SRIs in the rat hippocampus, we examined the effects of selective receptor antagonists on spontaneous fast current transients (CTs) recorded from these interneurons under cell-attached configuration. The frequency of CTs, which represent action potentials, increased in the absence of extracellular Mg(2*) and decreased in the presence of the alpha 3 beta 4 beta 2 nAChR antagonist mecamylamine (3 mu M) or the NMDA receptor antagonist APV (50 mu M). However, it was unaffected by the alpha 7 nAChR antagonist MLA (10 nM) or the AMPA receptor antagonist CNQX (10 mu M). Thus, in addition to synaptically and tonically activated NMDA receptors, alpha 3 beta 4 beta 2 nAChRs that are present on glutamatergic axons/neurons synapsing onto SRIs and are activated by basal levels of acetylcholine contribute to the maintenance of the excitability of these interneurons. Kynurenic acid (KYNA), an astrocyte-derived kynurenine metabolite whose levels are increased in the brains of patients with schizophrenia, also controls the excitability of SRIs. At high micromolar concentrations, KYNA, acting primarily as an NMDA receptor antagonist, decreased the CT frequency recorded from the interneurons. At 2 mu M, KYNA reduced the CA1 SRI excitability via mechanisms independent of NMDA receptor block. KYNA-induced reduction of excitability of SRIs may contribute to sensory gating deficits that have been attributed to deficient hippocampal GABAergic transmission and high levels of KYNA in the brain of patients with schizophrenia. (C) 2011 Published by Elsevier Inc.