Alkondon_2011_J.Pharmacol.Exp.Ther_337_572

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 alpha7 nicotinic acetylcholine receptors (nAChRs). The present in vitro study was designed to test the hypothesis that alpha7 nAChR activity decreases when endogenous production of KYNA increases. Incubation (2-7 h) of rat hippocampal slices with kynurenine (200 muM) 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 muM) and was more effective in slices from postweaned than preweaned rats. Incubation of slices from postweaned rats with kynurenine inhibited alpha7 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 muM). Exposure of human cerebral cortical slices to kynurenine also inhibited alpha7 nAChRs. The alpha7 nAChR sensitivity to KYNA is age-dependent, because neither endogenously produced nor exogenously applied KYNA inhibited alpha7 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 alpha7 nAChRs and extrasynaptic NMDARs are in close apposition to KYNA release sites and, thereby, readily accessible to inhibition by endogenously produced KYNA.