TY - JOUR
T1 - Double deletion of melanocortin 4 receptors and SAPAP3 corrects compulsive behavior and obesity in mice
AU - Xu, Pin
AU - Grueter, Brad A.
AU - Britt, Jeremiah K.
AU - McDaniel, Latisha
AU - Huntington, Paula J.
AU - Hodge, Rachel
AU - Tran, Stephanie
AU - Mason, Brittany L.
AU - Lee, Charlotte
AU - Vong, Linh
AU - Lowell, Bradford B.
AU - Malenka, Robert C.
AU - Lutter, Michael
AU - Pieper, Andrew A.
PY - 2013/6/25
Y1 - 2013/6/25
N2 - 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.
AB - 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.
KW - Anxiety disorders
KW - Conditional knockout mice
KW - Metabolism
KW - Synaptic transmission
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U2 - 10.1073/pnas.1308195110
DO - 10.1073/pnas.1308195110
M3 - Article
C2 - 23754400
AN - SCOPUS:84879549441
SN - 0027-8424
VL - 110
SP - 10759
EP - 10764
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 26
ER -