Double deletion of melanocortin 4 receptors and SAPAP3 corrects compulsive behavior and obesity in mice.

Proceedings of the National Academy of Sciences of the United States of America 2013 Jun 25

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Compulsive behavior is a debilitating clinical feature of many forms of neuropsychiatric disease, including Tourette syndrome, obsessive-compulsive spectrum disorders, eating disorders, and autism. Although several studies link striatal dysfunction to compulsivity, the pathophysiology remains poorly understood. Here, we show that both constitutive and induced genetic deletion of the gene encoding the melanocortin 4 receptor (MC4R), as well as pharmacologic inhibition of MC4R signaling, normalize compulsive grooming and striatal electrophysiologic impairments in synapse-associated protein 90/postsynaptic density protein 95-associated protein 3 (SAPAP3)-null mice, a model of human obsessive-compulsive disorder. Unexpectedly, genetic deletion of SAPAP3 restores normal weight and metabolic features of MC4R-null mice, a model of human obesity. Our findings offer insights into the pathophysiology and treatment of both compulsive behavior and eating disorders.

Citation

Pin Xu, Brad A Grueter, Jeremiah K Britt, Latisha McDaniel, Paula J Huntington, Rachel Hodge, Stephanie Tran, Brittany L Mason, Charlotte Lee, Linh Vong, Bradford B Lowell, Robert C Malenka, Michael Lutter, Andrew A Pieper. Double deletion of melanocortin 4 receptors and SAPAP3 corrects compulsive behavior and obesity in mice. Proceedings of the National Academy of Sciences of the United States of America. 2013 Jun 25;110(26):10759-64