Kynurenic acid inhibits glutamatergic transmission to CA1 pyramidal neurons via α7 nAChR-dependent and -independent mechanisms.
Glutamatergic hypofunction and elevated levels of kynurenic acid (KYNA) in the brain are common features of patients with schizophrenia. In vivo studies indicate that in the hippocampus KYNA decreases glutamate levels, presumably via inhibition of α7 nicotinic receptors (nAChRs). Here we tested the hypothesis that basal synaptic glutamate activity in the hippocampus is regulated by tonically active α7 nAChRs and is sensitive to inhibition by KYNA. To this end, spontaneous excitatory postsynaptic currents (EPSCs), sensitive to AMPA receptor antagonist CNQX (10 μM), were recorded from CA1 pyramidal neurons at -70 mV in rat hippocampal slices. The α7 nAChR antagonists α-bungarotoxin (α-BGT, 100 nM) and methyllycaconitine (MLA, 1-50 nM), and the NMDA receptor antagonist 2-amino-5-phosphonovaleric acid (APV, 50 μM) reduced the frequency of EPSCs. MLA and α-BGT had no effect on miniature EPSCs (mEPSCs). The effect of MLA decreased in the presence of APV (50 μM), with 1 nM MLA becoming completely ineffective. KYNA (1-20 μM) suppressed the frequency of EPSCs, without affecting mEPSCs. The effect of KYNA decreased in the presence of MLA (1 nM) or α-BGT (100 nM), with 1 μM KYNA being devoid of any effect. In the presence of both MLA (10 nM) and APV (50 μM) higher KYNA concentrations (5-20 μM) still reduced the frequency of EPSCs. These results suggest that basal synaptic glutamate activity in CA1 pyramidal neurons is maintained in part by tonically active α7 nAChRs and NMDA receptors and is inhibited by micromolar concentrations of KYNA, acting via α7 nAChR-dependent and -independent mechanisms.
Division of Translational Toxicology, Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Jyotirmoy
J
Banerjee
Manickavasagom
M
Alkondon
Edson X
EX
Albuquerque
D000818:Animals; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005971:Glutamates / Q000378:metabolism*; D066298:In Vitro Techniques; D007736:Kynurenic Acid / Q000494:pharmacology*; D008297:Male; D018733:Nicotinic Antagonists / Q000494:pharmacology; D017966:Pyramidal Cells / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000502:physiology*; D064569:alpha7 Nicotinic Acetylcholine Receptor
C579165:Chrna7 protein, rat; D005971:Glutamates; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D007736:Kynurenic Acid