Cyfip1 haploinsufficiency increases compulsive-like behavior and paternally inherited palatable food intake: Implications for Prader-Willi Syndrome

Abstract

Binge eating (BE) is a heritable trait associated with eating disorders and involves rapid consumption of large quantities of food. We identified cytoplasmic FMRP-interacting protein 2 (Cyfip2) as a major genetic factor underlying BE and concomitant compulsive-like behaviors in mice. CYFIP2 is a gene homolog of CYFIP1 - one of four paternally-deleted genes in patients with the more severe Type I Prader-Willi Syndrome (PWS). PWS is a neurodevelopmental disorder where 70% of cases involve paternal deletion of 15q11-q13. PWS symptoms include hyperphagia, obesity (if untreated), cognitive deficits, and obsessive-compulsive behaviors. We tested whether Cyfip1 haploinsufficiency (+/-) would enhance premorbid compulsive-like behavior and palatable food (PF) intake in a parent-of-origin-selective manner. We tested Cyfip1+/- mice on a C57BL/6N (N) background that were homozygous for the BE-associated missense mutation in Cyfip2 (S968F) as well as mice that we backcrossed to homozygosity for the C57BL/6J (J) allele at Cyfip2 (Cyfip2J/J). Cyfip1+/- mice showed increased compulsive-like behavior on both backgrounds, increased PF consumption on the Cyfip2N/N background in a paternally-enhanced manner, and decreased PF consumption in male Cyfip1+/- mice on the Cyfip2J/J background in a maternally selective manner. In the hypothalamus, there was a maternally-enhanced reduction of Cyfip1 transcription, but a paternally-enhanced reduction in CYFIP1 protein. In the nucleus accumbens, there was a maternally-enhanced reduction in CYFIP1 protein. Together, increased compulsive-like behavior, parent-of-origin-, and genetic background-dependent effects of Cyfip1 haploinsufficiency on PF consumption implicate CYFIP1 in behaviors in neurodevelopmental disorders involving reduced expression of CYFIP1, including PWS, Fragile X Syndrome, and 15q11.2 Microdeletion Syndrome.