PT - JOURNAL ARTICLE AU - Jyotirmoy Banerjee AU - Manickavasagom Alkondon AU - Edna F.R Pereira AU - Edson X. Albuquerque TI - Regulation of GABAergic inputs to CA1 pyramidal neurons by nicotinic receptors and kynurenic acid AID - 10.1124/jpet.111.189860 DP - 2012 Jan 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - jpet.111.189860 4099 - http://jpet.aspetjournals.org/content/early/2012/02/17/jpet.111.189860.short 4100 - http://jpet.aspetjournals.org/content/early/2012/02/17/jpet.111.189860.full AB - Impaired α7 nicotinic 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 schizhophrenia. KYNA acts as a non-competitive antagonist with respect to agonists at both α7 nAChRs and NMDA 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 antagonistα -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 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 somatodendritic and/or preterminal region of axons 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 about 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.