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

Biochem Pharmacol. 2011 Oct 15;82(8):842-51. doi: 10.1016/j.bcp.2011.06.004. Epub 2011 Jun 13.


CA1 stratum radiatum interneurons (SRIs) express α7 nicotinic receptors (nAChRs) and receive inputs from glutamatergic neurons/axons that express α3β4β2 nAChRs. To test the hypothesis that endogenously active α7 and/or α3β4β2 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 α3β4β2 nAChR antagonist mecamylamine (3 μM) or the NMDA receptor antagonist APV (50 μM). However, it was unaffected by the α7 nAChR antagonist MLA (10 nM) or the AMPA receptor antagonist CNQX (10 μM). Thus, in addition to synaptically and tonically activated NMDA receptors, α3β4β2 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 μM, 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Action Potentials / drug effects*
  • Animals
  • CA1 Region, Hippocampal / drug effects*
  • CA1 Region, Hippocampal / metabolism
  • Excitatory Amino Acid Antagonists / metabolism
  • Excitatory Amino Acid Antagonists / pharmacology*
  • In Vitro Techniques
  • Interneurons / drug effects*
  • Interneurons / metabolism
  • Kynurenic Acid / metabolism
  • Kynurenic Acid / pharmacology*
  • Male
  • Patch-Clamp Techniques
  • Protein Subunits
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Receptors, Nicotinic / metabolism*
  • Schizophrenia / metabolism


  • Excitatory Amino Acid Antagonists
  • Protein Subunits
  • Receptors, N-Methyl-D-Aspartate
  • Receptors, Nicotinic
  • Kynurenic Acid