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The Journal of Neuroscience, May 12, 2004, 24(19):4635-4648; doi:10.1523/JNEUROSCI.5631-03.2004

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Cellular/Molecular
Targeted Deletion of the Kynurenine Aminotransferase II Gene Reveals a Critical Role of Endogenous Kynurenic Acid in the Regulation of Synaptic Transmission via 7 Nicotinic Receptors in the Hippocampus

Manickavasagon Alkondon,^1 * Edna F. R. Pereira,^1 * Ping Yu,^2 * Emerson Z. Arruda,^1,3 * Luis E. F. Almeida,¹ Paolo Guidetti,⁴ William P. Fawcett,¹ Michael T. Sapko,⁴ William R. Randall,¹ Robert Schwarcz,^1,4 Danilo A. Tagle,² and Edson X. Albuquerque^1,3

¹Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland 21201, ²Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, ³Departamento de Farmacologia Básica e Clínica, Instituto de Ciências Biomédicas, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21944, Brazil, and ⁴Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, Maryland 21228

It has been postulated that endogenous kynurenic acid (KYNA) modulates 7^* nicotinic acetylcholine receptor (nAChR) and NMDA receptor activities in the brain.^a To test this hypothesis, 7^* nAChR and NMDA receptor functions were studied in mice with a targeted null mutation in the gene encoding kynurenine aminotransferase II (mKat-2^-/- mice), an enzyme responsible for brain KYNA synthesis. At 21 postnatal days, mKat-2^-/- mice had lower hippocampal KYNA levels and higher spontaneous locomotor activity than wild-type (WT) mice. At this age, 7^* nAChR activity induced by exogenous application of agonists to CA1 stratum radiatum interneurons was 65% higher in mKat-2^-/- than WT mice. Binding studies indicated that the enhanced receptor activity may not have resulted from an increase in 7^* nAChR number. In 21-d-old mKat-2^-/- mice, endogenous 7^* nAChR activity in the hippocampus was also increased, leading to an enhancement of GABAergic activity impinging onto CA1 pyramidal neurons that could be reduced significantly by acute exposure to KYNA (100 nM). The activities of GABA_A and NMDA receptors in the interneurons and of 34^* nAChRs regulating glutamate release onto these neurons were comparable between mKat-2^-/- and WT mice. By 60 d of age, KYNA levels and GABAergic transmission in the hippocampus and locomotor activity were similar between mKat-2^-/- and WT mice. Our findings that 7^* nAChRs are major targets for KYNA in the brain may provide insights into the pathophysiology of schizophrenia and Alzheimer's disease, disorders in which brain KYNA levels are increased and 7^* nAChR functions are impaired.

Key words: nicotinic receptors; kynurenic acid; NMDA receptors; GABA; hippocampus; mice

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Received Dec 21, 2003; revised March 29, 2004; accepted March 29, 2004.

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