Cyfip1 Haploinsufficiency Increases Compulsive-Like Behavior and Modulates Palatable Food Intake in Mice: Dependence on Cyfip2 Genetic Background, Parent-of Origin, and Sex

• Published in: G3 : genes - genomes - genetics Vol. 9; no. 9; pp. 3009 - 3022
• Main Authors: Babbs, Richard K, Beierle, Jacob A, Ruan, Qiu T, Kelliher, Julia C, Chen, Melanie M, Feng, Ashley X, Kirkpatrick, Stacey L, Benitez, Fabiola A, Rodriguez, Fred A, Pierre, Johanne J, Anandakumar, Jeya, Kumar, Vivek, Mulligan, Megan K, Bryant, Camron D
• Format: Journal Article
• Language: English
• Published: England Genetics Society of America 01.09.2019; Oxford University Press
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; addiction genetics; Animals; anorexia nervosa; Antigens, Neoplasm - genetics; Antigens, Neoplasm - metabolism; Appetite Regulation - genetics; Behavior, Animal - physiology; binge eating disorder; C57BL/6 substrains; Compulsive Behavior - genetics; Female; FMRP; Fragile X; Fragile X Mental Retardation Protein - metabolism; Genetics of Sex; Haploinsufficiency; Hypothalamus - metabolism; Male; Mice, Inbred C57BL; Mice, Knockout; neuropsychiatric; overeating; Proteins - genetics; Proteins - metabolism; psychiatric genetics; Reward; addiction genetics; psychiatric genetics; binge eating disorder; FMRP; neuropsychiatric; Genetics of Sex; overeating; C57BL/6 substrains; anorexia nervosa; Fragile X
• ISSN: 2160-1836; 2160-1836
• DOI: 10.1534/g3.119.400470

Binge eating (BE) is a heritable trait associated with eating disorders and involves episodes of rapid, large amounts of food consumption. We previously identified cytoplasmic FMR1-interacting protein 2 ( ) as a genetic factor underlying compulsive-like BE in mice. is a homolog of which is one of four paternally-deleted genes in patients with Type I Prader-Willi Syndrome (PWS), a neurodevelopmental disorder whereby 70% of cases involve paternal 15q11-q13 deletion. PWS symptoms include hyperphagia, obesity (if untreated), cognitive deficits, and obsessive-compulsive behaviors. We tested whether haploinsufficiency (+/-) would enhance compulsive-like behavior and palatable food (PF) intake in a parental origin- and sex-dependent manner on two genetic backgrounds, including the BE-prone C57BL/6N ( ) background and the BE-resistant C57BL/6J ( ) background. mice showed increased compulsive-like behavior on both backgrounds and increased PF intake on the background. In contrast, maternal haploinsufficiency on the BE-resistant background induced a robust escalation in PF intake in wild-type males while having no effect in males. Notably, induction of behavioral phenotypes in wild-type males following maternal has previously been reported. In the hypothalamus, there was a paternally-enhanced reduction in CYFIP1 protein whereas in the nucleus accumbens, there was a maternally-enhanced reduction in CYFIP1 protein. Nochange in FMR1 protein (FMRP) was observed in mice, regardless of parental origin. To summarize, haploinsufficiency increased compulsive-like behavior and induced genetic background-dependent, sex-dependent, and parent-of-origin-dependent effects on PF consumption and CYFIP1 expression that could have relevance for neurodevelopmental and neuropsychiatric disorders.