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

Abstract

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 (<i>Cyfip2</i>) as a genetic factor underlying compulsive-like BE in mice. <i>CYFIP2</i> is a homolog of <i>CYFIP1</i> 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 <i>Cyfip1</i> haploinsufficiency (+/-) would enhance compulsive-like behavior and palatable food (PF) intake in a parental origin- and sex-dependent manner on two <i>Cyfip2</i> genetic backgrounds, including the BE-prone C57BL/6N (<i>Cyfip2</i>^N/N) background and the BE-resistant C57BL/6J (<i>Cyfip2</i>^J/J) background. <i>Cyfip1</i>^+/- mice showed increased compulsive-like behavior on both backgrounds and increased PF intake on the <i>Cyfip2</i>^N/N background. In contrast, maternal <i>Cyfip1</i> haploinsufficiency on the BE-resistant <i>Cyfip2</i>^J/J background induced a robust escalation in PF intake in wild-type <i>Cyfip1</i>^J/J males while having no effect in <i>Cyfip1</i>^J/- males. Notably, induction of behavioral phenotypes in wild-type males following maternal <i>Fmr1</i>^+/- 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 <i>Cyfip1</i>^+/- mice, regardless of parental origin. To summarize, <i>Cyfip1</i> 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.