Neurodevelopmental disorders (NDDs), such as Intellectual Disability (ID) and Autism Spectrum Disorder (ASD) are more prevalent in males than females. Despite the fact the NDDs are diagnosed more frequently in males, the molecular mechanisms underlying sex bias in these disorders are still unknown. Until recently, sex had not been routinely considered in data analysis, and females were often excluded from behavioral experiments altogether. In parallel, for decades most genes identified for NDDs were on the X chromosome because of the relative ease to identify linkage regions in X-linked pedigrees, leading to mouse models that were studied only in one sex. Thus, testing of sex differences in preclinical animal models of NDDs has been limited. Our work introduces mice deficient for Coiled-coil and C2 domain containing 1a (Cc2d1a) as a novel mouse model for molecular and behavioral sex-specific deficits in NDDs. We found that CC2D1A loss of function (LOF) mutations cause ASD, ID and seizures in humans, and that Cc2d1a knock-out (KO) male mice display behavioral features of the human phenotype, including cognitive and social deficits, hyperactivity and anxiety. In contrast, our preliminary data show that female KO mice only present with milder cognitive deficits. Cc2d1a KO males also display a sex-specific reduction in CREB activation due a disregulation of the upstream PKA pathway. These findings raise the possibility that males and females may use different molecular strategies for encoding information and building neuronal circuits for the same behaviors, and in particular lead to our hypothesis that CC2D1A regulates CREB signaling in a sex-specific manner leading to sex-specific behavioral deficits. The overall goal of this proposal is to prove our hypothesis.
In Specific Aim 1 we will explore morphological, physiological and behavioral differences between male and female Cc2d1a KO mice which correlate with reduction in CREB signaling.
In Specific Aim 2 we will modulate the PKA/CREB pathway to demonstrate that all these phenotypes are connected by a sex-specific CREB signaling defect. Finally, in Specific Aim 3 we will explore the molecular mechanisms underlying sex-specific CC2D1A signaling. If successful our studies will identify a novel sexually dimorphic mechanisms for CREB signaling regulation and link molecular and cellular deficits to behavior. Our findings will be highly significant as they will establish the ID/ASD gene CC2D1A as a critical regulator of sex-specific signaling in the brain.
Neurodevelopmental disorders (NDDs) affecting cognitive and social function such intellectual disability (ID) and autism spectrum disorder (ASD) are more frequently diagnosed in males. The goal of this proposal is to characterize a novel animal model of NDDs where males are more severely affected and to define the molecular mechanisms leading to these sex-specific deficits.