The cellular and developmental basis of autism spectrum disorder (ASD) still represents a significant gap in our knowledge of this developmental disorder. To understand how ASD affects brain development, comprehensive disease models are needed. Such models will yield insight into the developmental programs that are affected in ASD and how these perturbations ultimately affect behavioral output.

Imbalances in excitatory versus inhibitory postsynaptic signaling in the central nervous system (CNS) have been associated with autism spectrum disorders (ASD). These imbalances are caused by mis-regulated chloride (Cl-) concentrations in the CNS. The potassium-chloride co-transporter is the key player involved in maintaining the low Cl- concentrations in neurons necessary for proper signaling. KCC2 is thus a potential target for therapeutic strategies aimed at rescuing excitatory/inhibitory imbalances in ASD and other disorders affected by such imbalances. However, targeted therapeutic strategies require detailed knowledge of the drug targets, and currently, there is insufficient biochemical information to target KCC2 using rational approaches.

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.