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Molecular and Cellular Biology, August 2004, p. 6919-6930, Vol. 24, No. 16
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.16.6919-6930.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Biochemical and Phenotypic Abnormalities in Kynurenine Aminotransferase II-Deficient Mice

Ping Yu,^1, Nicholas A. Di Prospero,^1, Michael T. Sapko,² Tao Cai,³ Amy Chen,¹ Miguel Melendez-Ferro,² Fu Du,² William O. Whetsell Jr.,⁴ Paolo Guidetti,² Robert Schwarcz,² and Danilo A. Tagle^1*

Genetics and Molecular Biology Branch, National Human Genome Research Institute,¹ Experimental Medicine Section, Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892,³ Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, Maryland 21228,² Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee 37235⁴

Received 23 February 2004/ Returned for modification 23 March 2004/ Accepted 26 May 2004

Kynurenic acid (KYNA) can act as an endogenous modulator of excitatory neurotransmission and has been implicated in the pathogenesis of several neurological and psychiatric diseases. To evaluate its role in the brain, we disrupted the murine gene for kynurenine aminotransferase II (KAT II), the principal enzyme responsible for the synthesis of KYNA in the rat brain. mKat-2^–/– mice showed no detectable KAT II mRNA or protein. Total brain KAT activity and KYNA levels were reduced during the first month but returned to normal levels thereafter. In contrast, liver KAT activity and KYNA levels in mKat-2^–/– mice were decreased by >90% throughout life, though no hepatic abnormalities were observed histologically. KYNA-associated metabolites kynurenine, 3-hydroxykynurenine, and quinolinic acid were unchanged in the brain and liver of knockout mice. mKat-2^–/– mice began to manifest hyperactivity and abnormal motor coordination at 2 weeks of age but were indistinguishable from wild type after 1 month of age. Golgi staining of cortical and striatal neurons revealed enlarged dendritic spines and a significant increase in spine density in 3-week-old mKat-2^–/– mice but not in 2-month-old animals. Our results show that gene targeting of mKat-2 in mice leads to early and transitory decreases in brain KAT activity and KYNA levels with commensurate behavioral and neuropathological changes and suggest that compensatory changes or ontogenic expression of another isoform may account for the normalization of KYNA levels in the adult mKat-2^–/– brain.

Present address: NCI—Frederick, Frederick, MD 21702.

Present address: NINDS, NIH, Bethesda, MD 20892.

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