This project proposes to perform single-nucleus RNA sequencing analysis of postmortem brain samples from children and adolescents with autism. The results will provide insight into region- and cell-type‐specific molecular changes in autism at an unprecedented level of resolution and should help to explain variations in disease phenotypes.

Macklis will directly investigate growth cone molecular machinery of cerebral cortex inter-hemispheric, associative, callosal projection neurons (CPN); abnormalities of CPN connectivity; and dose-dependent direct effects of aberrant cortical associative circuitry on social interaction behavior in mice mutant for the ASD risk gene Bcl11a/Ctip1.

Rubenstein will identify how defects in brain development are caused by ASD mutations in Pogz and Suv420h1, genes involved in chromatin remodeling and transcriptional silencing.

Sulzer will examine whether loss of the normal developmental maturation of striatal neuron excitability in ASD mouse models underlies striatal deficits.

Mourrain aims to identify common synaptic defects shared by different mouse genetic ASD models and to evaluate the efficacy of existing drugs on these synaptic changes.