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.

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.

Neuroimaging studies have described altered structural and functional connectivity across brain regions of individuals with autism spectrum disorder (ASD). These findings have led to the hypothesis that altered brain connectivity may provide a key pathophysiological contribution in ASD. However the neurobiological determinants and significance of these findings remain unclear.

The gene encoding the transcription factor FOXP1 is strongly implicated in the etiology of individuals with autism spectrum disorder (ASD) and of those with intellectual disability. FOXP1 is among the 40 highest-ranked candidate ASD risk genes (according to SFARI Gene). Brain-wide deletion of FOXP1 in mice results in altered behaviors relevant to ASD.

Autism spectrum disorders (ASDs) represent a group of neurodevelopmental disorders for which the underlying etiologies are heterogeneous. Risk factors range from environmental insults to single gene mutations. A unifying model explaining how this array of risk factors leads to deficits in communication, social interactions, and sensory and repetitive behavior is lacking.

The diagnostic dyad defining autism spectrum disorder (ASD) belies a tremendous phenotypic heterogeneity that remains a key challenge to diagnosis and treatment. The strong genetic component of ASD suggests that heterogeneity in underlying genetic mutations may contribute to phenotypic heterogeneity. However, the germline genetics of ASD has thus far proven insufficient to explain the clinical heterogeneity of the disorder.

Components of the mammalian target of rapamycin (mTOR) signaling pathway are key players in the pathogenesis of autism spectrum disorder (ASD). The mTOR pathway regulates protein homeostasis by promoting protein synthesis and inhibiting autophagy, a lysosomal degradation process that maintains protein quality control by breaking down cellular proteins and organelles to generate amino acids. Guomei Tang, David Sulzer and their colleagues at Columbia University Medical Center recently analyzed postmortem brain samples from individuals with ASD and discovered that, in response to hyperactive mTOR, autophagy was impaired in excitatory neurons. In animal models, autophagy deficiency causes ASD-like synapse pathology and social behaviors.

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.