d-Aspartate Regulates Melanocortin Formation and Function: Behavioral Alterations in d-Aspartate Oxidase-Deficient Mice
- Alex S. Huang1,
- Anne Beigneux4,*,
- Zachary M. Weil5,*,
- Paul M. Kim2,
- Mark E. Molliver1,
- Seth Blackshaw1,
- Randy J. Nelson5,**,
- Stephen G. Young4,**, and
- Solomon H. Snyder1,2,3
- Departments of 1Neuroscience, 2Pharmacology, and 3Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, 4Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, California 90095, and 5Departments of Psychology and Neuroscience, Institute for Behavioral Medicine Research, The Ohio State University, Columbus, Ohio 43210
Abstract
D-Aspartate, an abundant d-amino acid enriched in neuroendocrine tissues, can be degraded by d-aspartate oxidase (Ddo). To elucidate the function of d-aspartate, we generated mice with targeted deletion of Ddo (Ddo−/−) and observe massive but selective augmentations of d-aspartate in various tissues. The pituitary intermediate lobe, normally devoid of d-aspartate from endogenous Ddo expression, manifests pronounced increases of immunoreactive d-aspartate in Ddo−/− mice. Ddo−/− mice show markedly diminished synthesis and levels of pituitary proopiomelanocortin/α-MSH, associated with decreased melanocortin-dependent behaviors. Therefore, Ddo is the endogenous enzyme that degrades d-aspartate, and Ddo-enriched organs, low in d-aspartate, may represent areas of high turnover where d-aspartate may be physiologically important.
- Received November 18, 2005.
- Revision received January 16, 2006.
- Accepted January 17, 2006.
