Individuals who have very high cognitive and intellectual ability coupled with a diagnosis of autism are known as twice exceptional (2e). In partnership with the SFARI-funded SPARK initiative, Jacob Michaelson will recruit a cohort of 2e individuals with autism and collect genetic and neuroimaging data on these individuals in order to better understand the neurobiology of this underserved population.

Susanne Schmid will establish systematic and objective measures of sensory processing on the brain-stem level and on the cortical (perceptual) level that can be utilized in both children with ASD and a rodent model of ASD. Schmid expects that the development of these measures will provide better tools for diagnosing sensory-processing difficulties and will provide mechanistic insights that can aid in the development of pharmacological and behavioral treatments.

Rebecca Saxe will test whether midbrain dopaminergic signals of social cravings, previously observed in mice, are similarly observed in humans. As impairments in social motivation have been postulated to be a core social deficit in autism spectrum disorder (ASD), these results will improve the value of the mouse model for testing mechanisms of altered social motivation in ASD.

Tuberous sclerosis complex (TSC) and fragile X syndrome are syndromic neurogenetic disorders that have a high prevalence of ASD; however, the relationship between these two disorders at the cellular level has so far been largely unexplored. FMRP is known to be downregulated in neurons that lack TSC2. Mustafa Sahin plans to build on these findings and investigate the underlying mechanisms that are responsible for downregulating FMRP expression, using both induced pluripotent stem cells from individuals with tuberous sclerosis complex and Tsc2-deficient mice.

Carol Mason’s laboratory recently identified atypical refinement of neurons in the developing visual system in Fmr1 mutant mice. Here, in collaboration with Mimi Shirasu-Hiza’s laboratory, she proposes to investigate whether FMR1 in astrocytes plays a role in this phenotype and to identify the cell-type specific transcriptional changes related to this effect.

Frank McCormick will address the biochemical mechanism by which mutations in SYNGAP1 drive ASD and intellectual disability. Elucidation of the mechanism of SYNGAP1 negative regulation of RAS and its effector pathways in neurons will further our understanding of the role of this pathway in health and disease, and will shed light on potential ways in which targeted RAS pathway inhibition may be therapeutically relevant.

The mitochondrial genome encodes genes critical for energy production within the brain. Many lines of evidence suggest that mitochondrial function may be impaired in autism. Neal Sondheimer will evaluate the association between mitochondrial mutations and their interactions with the nuclear genome and the risk for autism.

Chaste will use genomic prediction to assess the relationship between genetic risk for ASD and autistic traits in the general population.

Sachin Patel will test the hypothesis that insular cortical projections to the central amygdala serve to reduce social interaction and alter pain processing, with the goal of understanding whether alterations in this circuit underlie impairments in social and pain processing behaviors in ASD.

Haploinsufficiency in SCN2A is among the most common risk factors for autism spectrum disorder (ASD). Using Scn2a heterozygous mice, the Ahituv lab will utilize CRISPR activation (CRISPRa) technologies to upregulate Scn2a expression and assess whether synaptic function deficits can be rescued. This work will provide insights into the therapeutic potential of CRISPRa-mediated gene therapy to treat ASD resulting from Scn2a loss-of-function variants and potentially other haploinsufficient genetic mutations.