High-confidence autism risk genes fall within several distinct functional categories, which include synaptic genes, WNT pathway genes and genes encoding chromatin remodeling factors. How these different functional categories relate to each other remains largely unknown. One prevailing hypothesis is that all of these mutations converge on a limited number of critical molecular pathways and cellular mechanisms to ultimately disrupt excitatory:inhibitory (E:I) balance in autism-associated brain circuits.
In the current project, Albert Basson and Laura Andreae propose to test this hypothesis in the context of one of these genes, CHD8, which encodes a chromatin remodeling factor. With support from a previous SFARI Pilot Award, Basson’s group has been assessing the effects of reductions in, or loss of, Chd8 function. Findings from their studies demonstrate altered neocortical gene expression, brain overgrowth and functional over-connectivity in Chd8 haploinsufficient mice. More recently, they have also demonstrated dosage-sensitive functions for Chd8 during mouse cortical development.
Basson and Andreae have also uncovered evidence suggesting direct functional links between Chd8 deficiency, altered proliferation of specific progenitors in the mid-gestation cortex and circuit changes. They hypothesize that these early alterations are responsible for altered E:I balance in Chd8 heterozygous mice. To test this hypothesis, they plan to establish a system for reducing Chd8 expression within individual neuronal subtypes and assessing the distinct effects that these cell-type specific reductions have on excitatory and inhibitory synaptic transmission across neurodevelopment.
Findings from these studies will help to shed light on how Chd8 mutations disrupt autism-relevant circuits in the developing cortex.
