Chiara Manzini of the Child Health Institute of New Jersey and the Rutgers Robert Wood Johnson Medical School will present a lecture entitled: Male-specific intracellular signaling and male bias in neurodevelopmental disorders.
Abstract: The molecular mechanisms for sex differences in establishing cognitive function in males and females are poorly understood. The higher incidence of males diagnosed with neurodevelopmental disorders (NDDs) such as intellectual disability (ID) and autism spectrum disorder (ASD) has led to theories proposing that male are more susceptible to NDDs because of elevated levels of fetal testosterone, and/or females are protected by unknown mechanisms. However, to date, no theory has definite support, because we lack models for NDDs where sexually dimorphic cellular responses and behavior can be identified and manipulated. Discovering the mechanisms underlying sex differences in ASD/ID, and in circuit development in general, is critical to understand this disorder. We must determine whether the same molecular deficit could lead to distinct outcomes and circuit alterations in males and females. It is possible that therapeutic approaches will need to be sex-specific.
Our work introduces a mouse model to begin addressing sex bias in ASD/ID using mice deficient for Coiled-coil and C2 domain containing 1a (Cc2d1a). Cc2d1a is a promiscuous signaling scaffold regulating the activity-dependent transcription factor CREB, which has a critical role in learning and memory. We found that CC2D1A loss of function (LOF) mutations in humans cause ID, ASD, and seizures. Cc2d1a-deficient male mice show behavioral features of the human phenotype, including cognitive deficits in spatial memory and object memory, reduced sociability, hyperactivity and anxiety. In contrast, female mice lack only the ability to identify novel objects, but show no other behavioral deficit. In parallel, we found that CREB signaling are altered in the hippocampus of Cc2d1a-deficient males, but not females. These differences are observed in both the adult brain and primary neuronal cultures obtained from male and female embryos, suggesting that this molecular differences are established very early in development.
We propose that Cc2d1a regulates behavior by controlling intracellular signaling in a sex-specific manner. This could represent a novel molecular mechanism establishing sex differences in cognitive function and circuit formation. Our long term goal is to explore whether these sexually dimorphic molecular mechanisms contribute to sex bias in NDDs in other animal models and in humans..