Cyfip1 Haploinsufficiency Increases Compulsive-Like Behavior and Modulates Palatable Food Intake in Mice: Dependence on Cyfip2 Genetic Background, Parent-of Origin, and Sex.
Document Type
Article
Publication Date
9-4-2019
Keywords
JMG
JAX Source
G3 (Bethesda) 2019 Sep 4; 9(9):3009-3022
Volume
9
Issue
9
First Page
3009
Last Page
3022
ISSN
2160-1836
PMID
31324746
DOI
https://doi.org/10.1534/g3.119.400470
Grant
DA041668
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 (Cyfip2) as a genetic factor underlying compulsive-like BE in mice. CYFIP2 is a homolog of CYFIP1 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 Cyfip1 haploinsufficiency (+/-) would enhance compulsive-like behavior and palatable food (PF) intake in a parental origin- and sex-dependent manner on two Cyfip2 genetic backgrounds, including the BE-prone C57BL/6N (Cyfip2 N/N) background and the BE-resistant C57BL/6J (Cyfip2 J/J) background. Cyfip1 +/- mice showed increased compulsive-like behavior on both backgrounds and increased PF intake on the Cyfip2 N/N background. In contrast, maternal Cyfip1 haploinsufficiency on the BE-resistant Cyfip2 J/J background induced a robust escalation in PF intake in wild-type Cyfip1 J/J males while having no effect in Cyfip1 J/- males. Notably, induction of behavioral phenotypes in wild-type males following maternal Fmr1 +/- 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 Cyfip1 +/- mice, regardless of parental origin. To summarize, Cyfip1 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.
Recommended Citation
Babbs R,
Beierle J,
Ruan Q,
Kelliher J,
Chen M,
Feng A,
Kirkpatrick S,
Benitez F,
Rodriguez F,
Pierre J,
Anandakumar J,
Kumar V,
Mulligan M,
Bryant C.
Cyfip1 Haploinsufficiency Increases Compulsive-Like Behavior and Modulates Palatable Food Intake in Mice: Dependence on Cyfip2 Genetic Background, Parent-of Origin, and Sex. G3 (Bethesda) 2019 Sep 4; 9(9):3009-3022