This team will investigate the deubiquitinating factor as a ‘hub’ risk factor for ASD, and elucidate how it acts to mediate cortical development and function.

Gymrek aims to leverage bioinformatics advances in analyzing complex genetic variants to comprehensively evaluate the role of de novo DNA repeat variants in autism spectrum disorder.

A number of studies have lead to the suggestion that disruptions to chloride homeostasis play a role in a variety of neurological and neurodevelopmental disorders. The neuron-specific potassium chloride co-transporter, KCC2, is the major chloride exporter in neuronal cells, and mutations in SLC12A5 (the gene encoding KCC2) have been reported in individuals with some neurodevelopmental disorders, such as autism spectrum disorder (ASD), epilepsy and schizophrenia. Further, results from KCC2 knockout and knockdown mice highlight the importance of this protein in proper neuronal function.

Little is known or understood about the molecular mechanisms responsible for social cognitive development and the diseases associated with its aberrations, such as autism spectrum disorder (ASD). Monitoring the concentration profile of molecules that are implicated in ASD is necessary to close a crucial understanding gap: how an organism’s social environment affects molecular-scale changes in the brain and corresponding alterations in social cognition. The key limitation in closing this gap hinges on sensors for neurohormones, such as oxytocin, implicated in social disorders.

Alfred George will employ an automated electrophysiology system to elucidate the functional consequences of a large set of SCN2A variants of unknown clinical significance associated with neurodevelopmental disorders, including autism and epilepsy.

Several key barriers exist to unraveling the mechanistic etiologies of autism spectrum disorder (ASD). There is increasing appreciation that ASD pathology, while genetically heterogeneous, may result from disruptions to common multicellular interactions that impact cortical circuitry and alter excitatory/inhibitory (E/I) balance. Duplication or triplication of maternally inherited 15q11-13, the chromosomal location where UBE3A resides, is one of the most common genetic variants linked to ASD. UBE3A is an E6 ubiquitin ligase that controls the levels of key synaptic proteins, and UBE3A activity has been shown to control E/I balance in the cerebral cortex of mice.

Genetic risks for autism are diverse and encompass mutations and copy number variations in hundreds of genes. However, autism is diagnosed through the evaluation of a shared set of symptoms that include social interaction deficits and repetitive or restrictive behaviors.

Anthony Wynshaw-Boris and his colleagues are investigating the hypothesis that a subset of individuals with autism spectrum disorders (ASD) (approximately 25-30 percent) display early brain overgrowth. His lab has recently produced two relevant models that recapitulate important aspects of early brain overgrowth in ASD. First, the team produced a mouse model deficient for DVL1 and DVL3 (Dvl1/3 +/– mutants). These mice display adult social behavior abnormalities associated with transient embryonic brain enlargement during the time of deep-layer cortical formation. Second, they generated human induced pluripotent stem cell (iPSC) models by reprogramming fibroblasts obtained from individuals with ASD who had early head overgrowth and unaffected control individuals with normal head circumference. Neuronal progenitor cells (NPCs) derived from ASD iPSC lines displayed enhanced proliferation compared to control NPCs. In both the Dvl 1/3 mutant mouse model and the human iPSCs, the observed phenotypes were caused by down-regulation of beta-catenin activity and its direct target BRN2. This remarkable conservation of beta-catenin and BRN2 signaling disruption in different models of ASD suggests that multiple variants contributing to ASD may converge on common pathways.

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.