title: Double deletion of melanocortin 4 receptors and SAPAP3 corrects compulsive behavior and obesity in mice.
abstract: 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.
authors.affiliation: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Pin
authors.initials: P
authors.lastname: Xu
authors.forename: Brad A
authors.initials: BA
authors.lastname: Grueter
authors.forename: Jeremiah K
authors.initials: JK
authors.lastname: Britt
authors.forename: Latisha
authors.initials: L
authors.lastname: McDaniel
authors.forename: Paula J
authors.initials: PJ
authors.lastname: Huntington
authors.forename: Rachel
authors.initials: R
authors.lastname: Hodge
authors.forename: Stephanie
authors.initials: S
authors.lastname: Tran
authors.forename: Brittany L
authors.initials: BL
authors.lastname: Mason
authors.forename: Charlotte
authors.initials: C
authors.lastname: Lee
authors.forename: Linh
authors.initials: L
authors.lastname: Vong
authors.forename: Bradford B
authors.initials: BB
authors.lastname: Lowell
authors.forename: Robert C
authors.initials: RC
authors.lastname: Malenka
authors.forename: Michael
authors.initials: M
authors.lastname: Lutter
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Pieper
mesh_terms: D000818:Animals; D001835:Body Weight; D003192:Compulsive Behavior / Q000503:physiopathology* / Q000517:prevention & control; D003342:Corpus Striatum / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D006120:Grooming / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics*; D009765:Obesity / Q000503:physiopathology* / Q000517:prevention & control; D010456:Peptides, Cyclic / Q000494:pharmacology; D044105:Receptor, Melanocortin, Type 4 / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D009435:Synaptic Transmission / Q000502:physiology
chemical_list: C116941:HS014 cyclic peptide; C574273:MC4R protein, mouse; D009419:Nerve Tissue Proteins; D010456:Peptides, Cyclic; D044105:Receptor, Melanocortin, Type 4; C523020:Sapap3 protein, mouse
keywords: anxiety disorders; conditional knockout mice; metabolism; synaptic transmission