Exploring sex differences in autism via the NRXN1 knockout rat

Autism spectrum disorder (ASD) is diagnosed in boys 4-5 times more frequently than in girls. Many factors contribute to this gender bias, but the origins of the biological factors remain largely unknown. Sex differences in the expression of candidate risk genes may underlie at least some of this bias, but these differences have not been explored.

The preoptic area (POA) is a sexually dimorphic brain region critical to the control of nurturing behavior. It is also known to be reciprocally connected with brain regions that regulate empathy, social play and fear. Yet the POA has received little consideration in the context of ASD. Neurexin 1 (NRXN1) is a cell adhesion molecule that is highly expressed in the POA and has shown robust sex differences in the neonatal rat. Loss-of-function mutations in the NRXN1 gene are found in as many as 0.5 percent of individuals with ASD, making it among the most robust ASD risk gene candidates identified to date.

In the current project, Margaret McCarthy plans to use the NRXN1 knockout rat to examine how sex differences in expression of the NRXN1 gene drive social behaviors. McCarthy’s group will focus on the hypothalamus and the POA. The study aims to determine the impact of NRXN1 haploinsufficiency on known sex differences in gene expression, synaptic patterning and cell number in the POA, and to introduce new behavioral tests in young rats and determine the impact of NRXN1 deficiency on those behaviors. The results of this study will help identify potential biological contributions to ASD gender bias.