RT Journal Article
SR Electronic
T1 Age dependency of inhibition of α7 nicotinic receptors and tonically active NMDA receptors by endogenously produced kynurenic acid in the brain
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.110.177386
DO 10.1124/jpet.110.177386
A1 Manickavasagom Alkondon
A1 Edna R Pereira
A1 Howard M Eisenberg
A1 Yasushi Kajii
A1 Robert Schwarcz
A1 Edson X. Albuquerque
YR 2011
UL http://jpet.aspetjournals.org/content/early/2011/01/26/jpet.110.177386.abstract
AB 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 α7 nicotinic receptors (nAChRs). The present in vitro study was designed to test the hypothesis that α7 nAChR activity decreases when endogenous production of KYNA increases. Incubation (2-7 h) of rat hippocampal slices with kynurenine (200 µM) resulted in continuous de novo synthesis of KYNA. Kynurenine conversion to KYNA was significantly decreased by the KAT II inhibitor BFF122 (100 µM) and was more effective in slices from post- than pre-weaned rats. Incubation of slices from post-weaned rats with kynurenine inhibited α7 nAChRs and extrasynaptic NMDARs on CA1 stratum radiatum interneurons. These effects were attenuated by BFF122 and mimicked by exogenously applied KYNA (200 µM). Exposure of human cerebral cortical slices to kynurenine also inhibited α7 nAChRs. The α7 nAChR sensitivity to KYNA is age dependent, because neither endogenously produced nor exogenously applied KYNA inhibited α7 nAChRs in slices from pre-weaned 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 pre- and post-weaned 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 α7 nAChRs and extrasynaptic NMDARs are in close apposition to KYNA release sites and, thereby, readily accessible to inhibition by endogenously produced KYNA.