GABAergic neuronal signaling is essential in the development and basic functioning of the nervous system. Maintaining an appropriate balance between neuronal excitation and inhibition is a complex task that involves the modulation of inhibitory GABAergic signaling. Vertebrate GABAergic neurons can undergo synaptic and structural plasticity during and after development through the dynamic remodeling of dendrites, axons and synaptic boutons. This structural remodeling is critical in maintaining inhibitory homeostasis and is likely instrumental in the pathogenesis of many neurological conditions, including autism spectrum disorder (ASD).
Despite the importance of GABAergic structural plasticity to basic neurobiology and likely to human disease, little is understood about the function, impact or molecular mechanisms involved, or its impact on human disease pathogenesis. Work in this area has been hindered by the lack of an accessible and relevant model in which to study the complex process of GABAergic structural plasticity.
In the current project, Michael Hart plans to identify novel roles for known ASD risk genes in GABAergic structural plasticity. He will do this by studying the morphological plasticity, connectivity and behavioral output of the GABAergic DVB neuron in adult C. elegans with null or loss-of-function mutant alleles in orthologs of ASD risk genes. He also plans to create ‘humanized’ C. elegans models that express human ASD risk genes in C. elegans that lack the worm orthologs and to assess whether the observed GABAergic structural plasticity deficits can be rescued and the impact of variants. Lastly, unbiased forward genetic screens in C. elegans will be used to identify novel genes and pathways that regulate and modify GABAergic structural plasticity.
Taken together, findings from these studies may lead to a better understanding of neuronal and circuit plasticity changes associated with ASD pathogenesis.