Age Dependency of Inhibition of 7 Nicotinic Receptors and Tonically Active N-Methyl-D-aspartate Receptors by Endogenously Produced Kynurenic Acid in the Brain

In the mouse hippocampus normal levels of kynurenic acid (KYNA), a neuroactive metabolite synthesized in astrocytes primarily by kynurenine aminotransferase II (KAT II)-catalyzed transamination of L-kynurenine, maintain a degree of tonic inhibition of 7 nicotinic acetylcholine receptors (nAChRs). The present in vitro study was designed to test the hypothesis that 7 nAChR activity decreases when endogenous production of KYNA increases. Incubation (2–7 h) of rat hippocampal slices with kynurenine (200 M) resulted in continuous de novo synthesis of KYNA. Kynurenine conversion to KYNA was significantly decreased by the KAT II inhibitor (S)-( )-9-(4-aminopiperazine-1-yl)8-fluoro-3-methyl-6-oxo-2,3,5,6-tetrahydro-4H-1-oxa-3a-azaphenalene-5carboxylic acid (BFF122) (100 M) and was more effective in slices from postweaned than preweaned rats. Incubation of slices from postweaned rats with kynurenine inhibited 7 nAChRs and extrasynaptic N-methyl-D-aspartate receptors (NMDARs) on CA1 stratum radiatum interneurons. These effects were attenuated by BFF122 and mimicked by exogenously applied KYNA (200 M). Exposure of human cerebral cortical slices to kynurenine also inhibited 7 nAChRs. The 7 nAChR sensitivity to KYNA is age-dependent, because neither endogenously produced nor exogenously applied KYNA inhibited 7 nAChRs in slices from preweaned rats. In these slices, kynurenine-derived KYNA also failed to inhibit extrasynaptic NMDARs, which could, however, be inhibited by exogenously applied KYNA. In slices from preweaned and postweaned rats, glutamatergic synaptic currents were not affected by endogenously produced KYNA, but were inhibited by exogenously applied KYNA. These results suggest that in the mature brain 7 nAChRs and extrasynaptic NMDARs are in close apposition to KYNA release sites and, thereby, readily accessible to inhibition by endogenously produced KYNA.