Mutations in hundreds of genes may predispose individuals to autism, but no common feature characterizes these genes, little is known about the functions of many of them and it remains unclear how mutations in these genes promote autism pathogenesis. Multiple autism-associated mutations have been identified in genes encoding neuroligins — cell-adhesion molecules that are essential for the organization of synapses, or the junctions between neurons, and for synapse property specification, during which neuroligins contribute to organizing synapse properties.
The overall hypothesis of this project is that mutations in neuroligins and other genes promote autism pathogenesis by impairing the functions of specific neural circuits. Identifying these impairments may lead to a better understanding of autism and the development of new therapies. To address this hypothesis, Thomas Südhof and his colleagues at Stanford University in California plan to use genetic mice as a model system to impair neuroligin function in two key areas of the brain implicated in autism: the medial prefrontal cortex and the striatum. The researchers aim to analyze the effects of these impairments with a combination of electrophysiological, imaging and behavioral assays.
Südhof and his team plan to identify specific changes in neural circuits that cause a particular autism-relevant behavioral impairment. They hope to test whether the changes are reversible after development, in order to determine whether they are potentially treatable.
The group plans to examine whether different neuroligin mutations have similar effects, in order to understand whether there is a common pathway that mediates the development of autism-relevant behavioral impairments caused by different mutations. The researchers hope that these experiments, although focused on only two brain areas and one set of genes with a rare frequency of mutations, may provide paradigmatic insights into how different gene mutations can produce specific synaptic and circuit dysfunctions that in turn promote particular autism-relevant behavioral impairments.