SFARI

Neuronal activity triggers the expression of new genes that play a critical role in aspects of neural development and cognitive function. Building on evidence suggesting links between a class of ASD susceptibility loci (i.e., subunits of the BAF chromatin remodeling complex) and this form of gene regulation, Michael Greenberg and colleagues seek to determine whether disruption in neuronal activity-responsive chromatin remodeling underlies the effects of these ASD mutations.

Genetic studies of ASD implicate alterations in synaptic development and signaling, with the synaptic protein neurexin-1 playing a pivotal role. Ann Marie Craig aims to develop new approaches to overcome neurexin-1-linked synaptic deficits in ASD by modulating the remaining NRXN1 allele to boost neurexin-1 function and restore synaptic structure and function.

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.

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.

The neuron-specific potassium-chloride co-transporter, KCC2, is involved in the regulation of excitatory and inhibitory neuronal activity. It has been identified as a promising therapeutic target for autism. In the current project, Charles Craik’s laboratory and collaborators plan to determine the high-resolution structure of KCC2 with the intention of developing strategies to regulate its activity.

Crabtree and Gleeson will focus on rare high-impact genetic mutations for factors in the BAF complex to test how links between neuronal activity and the epigenome may be interrupted in ASD.

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.

SPARK (Simons Foundation Powering Autism Research for Knowledge) is an autism research initiative that aims to recruit, engage and retain a community of 50,000 individuals with autism and their family members living in the U.S. Participation in this cohort will involve contribution of medical and behavioral information, mailing in saliva for genetic analysis, the potential option to have genetic findings related to autism returned, and consenting to be invited to participate in future research studies.

Recent studies have provided compelling evidence that loss-of-function mutations in the CHD8 gene, which encodes an ATP-dependent chromatin-remodeling factor, are associated with an autism subtype characterized by macrocephaly, specific craniofacial features and gut immobility. The CHD8 protein modifies the structure of chromatin in the cell nucleus, and in vitro studies have suggested that CHD8 might function as a regulator of the developmentally important Wnt and PTEN signaling pathways. Tight control of both of these pathways is critical for normal brain development, and mutations that affect their activity have been strongly associated with autism and brain size. It is therefore important to test whether CHD8 functions as a regulator of these pathways during brain development.

Autism arises in early childhood, during a period of intense learning when many of the brain’s connections are modified by experience. Several autism-associated proteins also play important roles in memory formation.