Autism spectrum disorders (ASDs) are a group of pervasive neurodevelopmental disorders affecting approximately 1 in 59 children born in the United States. There has been a dramatic growth in our understanding of the genetic basis for ASDs over the past several years, and many rare de novo gene variants have been discovered that contribute to the disorder. However, we are still at an early stage of determining how these gene mutations underlie the cognitive and behavioral impairments in ASDs.

Engineering mouse models with construct and face validity for ASDs is a critical first step in developing our understanding of the cellular, synaptic and circuit alterations in ASDs. Of particular importance are the development of models in which mutations with a known functional consequence are created so that specific hypotheses can be tested and potential signaling pathways probed for the development of potential therapies. Moreover, understanding disruptions in circuit activity and brain physiology in mouse models is the first step in determining whether there are convergent phenotypes across this heterogeneous disorder.

In this study, Anis Contractor’s laboratory plans to bridge techniques and disciplines to validate a novel mouse model for ASDs that has a gain-of-function mutation in the alpha1 pore-forming subunit of the voltage-gated calcium channel Ca_v1.3 (Cacna1d[G407R] knock-in mice). The project will determine how this known ASD-associated mutation disrupts the normal development of neuronal morphology, synaptic properties and plasticity of neurons in the striatum, an area of the brain known to be important for habit formation. Correlating these cellular and synaptic findings with imaging of neuronal activity in vivo and behavioral studies will allow Contractor’s group to build a comprehensive understanding of the effects of this mutation in the Ca_v1.3 channel on striatal circuitry. The description of circuit-level alterations in this new mouse model will be a first step in translational efforts to bring forward new therapeutic approaches for ASDs.