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

Abstract

Binge eating (BE) is a heritable trait associated with eating disorders and involves consumption of a large quantity of food in a short time. 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 genetic disorder where 70% of cases involve paternal deletion of 15q11-q13. PWS is defined phenotypically by the emergence of hyperphagia and obesity during childhood as well as cognitive deficits and obsessive-compulsive behaviors. We tested the hypothesis that Cyfip1 haploinsufficiency would enhance premorbid compulsive-like behavior and palatable food (PF) consumption in a parent-of-origin-selective manner.Additionally, because our initial studies involved mice on a C57BL/6N background that possess the BEassociated missense mutation in Cyfip2, we tested mice on a mixed background where mice were homozygous for the C57BL/6J (B6J) allele at the Cyfip2 locus. Cyfip1 haploinsufficiency increased compulsive-like behavior on both backgrounds and PF consumption was greater with paternal inheritance. Gene expression in the hypothalamus revealed a paternal effect of Cyfip1 deletion on transcription of Cyfip1 but not Cyfip2 or Magel2. To summarize, the selective increased compulsive-like behavior and PF consumption in paternally deleted Cyfip1 +/-mice could translate to enhancing hyperphagia in a subset of individuals with neurodevelopmental disorders involving reduced expression or haploinsufficiency of CYFIP1, including PWS but also Fragile X Syndrome and 15q11.2 Microdeletion Syndrome.

Parent-of-Origin Effects in 15q11.2 BP1-BP2 Microdeletion (Burnside-Butler) Syndrome

“…More recently, CYFIP1 gene expression in murine brain tissue and expression patterns are dependent on the POE of the deletion. For example, paternal loss of the CYFIP1 gene was associated with lower protein expression in the hypothalamus, while maternal loss was associated with lower expression in the nucleus accumbens [33]. In this study, the effect of certain CYFIP2 variants was tested and the expression patterns were dependent on the gender of the mice.…”

“…One possibility for the associated phenotypes with a maternal POE is the maternal CYFIP1 gene allele is preferentially expressed in different brain tissue(s) and a loss of the maternal allele is more detrimental than loss of the paternal allele in these tissues, which may somehow disrupt FMR1 and/or RAC1 activities or the WAVE regulatory complex. In one study using a mouse model, there was evidence for maternal expression of CYFIP1 in the nucleus accumbens [33]. Further, Abekhoukh and colleagues [32] noted that previous studies found inconsistent neural spine phenotypes when observing CYFIP1 -deficient mice.…”

Genetic differences in the behavioral organization of binge eating, conditioned food reward, and compulsive-like eating in C57BL/6J and DBA/2J strains

“…Because of the link between anxiety, compulsivity and pathological overeating [41] and because obsessive-compulsive behavior is associated with eating disorders [42, 43], following the identification of parental strain differences in BE, we developed a behavioral battery to assess differences in premorbid anxiety-like and compulsive-like behaviors [44] that we applied toward experimentally naïve F 2 mice. A subset of the F 2 mice we generated (92 out of 132 mice total) were tested in the behavioral battery during the first week of testing with one test per day over five days in the following order: 1) open field; 2) elevated plus maze; 3) marble burying; 4) hole board; 5) y-maze.…”

Genetic differences in the behavioral organization of binge eating, conditioned food reward, and compulsive-like eating in C57BL/6J and DBA/2J strains

“…Because of the link between anxiety, compulsivity and pathological overeating [38] and because obsessive-compulsive behavior is associated with eating disorders [39,40], following the identification of parental strain differences in BE, we developed a behavioral battery to assess differences in premorbid anxiety-like and compulsive-like behaviors [41] that we applied toward experimentally naïve F 2 mice. A subset of the F 2 mice we generated (92 out of 132 mice total) were tested in the behavioral battery during the first week of testing with one test per day over five days in the following order: 1) open field; 2) elevated plus maze; 3) marble burying; 4) hole board; 5) y-maze.…”

“…Post hoc one-or two-way ANOVA and Welch's unequal variances t tests (p < 0.05, Bonferroni-corrected) were also conducted to determine effects on individual days. Slope analysis of normalized food intake across the food training days was conducted to quantify escalation [18,25,41,42]. Due to a video recording failure caused by insufficient computer storage space, non-ingestive behaviors (time on, number of visits to, and mean visit time on the light side) on D23 were not obtained in 8 of the 16 PF-trained F 1 mice.…”