title: Regulation of GABAergic inputs to CA1 pyramidal neurons by nicotinic receptors and kynurenic acid.
abstract: Impaired α7 nicotinic acetylcholine receptor (nAChR) function and GABAergic transmission in the hippocampus and elevated brain levels of kynurenic acid (KYNA), an astrocyte-derived metabolite of the kynurenine pathway, are key features of schizophrenia. KYNA acts as a noncompetitive antagonist with respect to agonists at both α7 nAChRs and N-methyl-D-aspartate receptors. Here, we tested the hypothesis that in hippocampal slices tonically active α7 nAChRs control GABAergic transmission to CA1 pyramidal neurons and are sensitive to inhibition by rising levels of KYNA. The α7 nAChR-selective antagonist α-bungarotoxin (α-BGT; 100 nM) and methyllycaconitine (MLA; 10 nM), an antagonist at α7 and other nAChRs, reduced by 51.3 ± 1.3 and 65.2 ± 1.5%, respectively, the frequency of GABAergic postsynaptic currents (PSCs) recorded from CA1 pyramidal neurons. MLA had no effect on miniature GABAergic PSCs. Thus, GABAergic synaptic activity in CA1 pyramidal neurons is maintained, in part, by tonically active α7 nAChRs located on the preterminal region of axons and/or the somatodendritic region of interneurons that synapse onto the neurons under study. L-Kynurenine (20 or 200 μM) or KYNA (20-200 μM) suppressed concentration-dependently the frequency of GABAergic PSCs; the inhibitory effect of 20 μM L-kynurenine had an onset time of approximately 35 min and could not be detected in the presence of 100 nM α-BGT. These results suggest that KYNA levels generated from 20 μM kynurenine inhibit tonically active α7 nAChR-dependent GABAergic transmission to the pyramidal neurons. Disruption of nAChR-dependent GABAergic transmission by mildly elevated levels of KYNA can be an important determinant of the cognitive deficits presented by patients with schizophrenia.
authors.affiliation: Division of Translational Toxicology, Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Jyotirmoy
authors.initials: J
authors.lastname: Banerjee
authors.forename: Manickavasagom
authors.initials: M
authors.lastname: Alkondon
authors.forename: Edna F R
authors.initials: EF
authors.lastname: Pereira
authors.forename: Edson X
authors.initials: EX
authors.lastname: Albuquerque
mesh_terms: D000157:Aconitine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002038:Bungarotoxins / Q000494:pharmacology; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism*; D059330:GABAergic Neurons / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D007736:Kynurenic Acid / Q000378:metabolism*; D007737:Kynurenine / Q000494:pharmacology; D008297:Male; D018733:Nicotinic Antagonists / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012559:Schizophrenia / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects; D013779:Tetrodotoxin / Q000494:pharmacology; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D002038:Bungarotoxins; C579165:Chrna7 protein, rat; D018733:Nicotinic Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D011978:Receptors, Nicotinic; D026941:Sodium Channel Blockers; D064569:alpha7 Nicotinic Acetylcholine Receptor; C054634:methyllycaconitine; D007737:Kynurenine; D013779:Tetrodotoxin; D007736:Kynurenic Acid; D000157:Aconitine