Failure of Homeostatic Plasticity Caused By Novel Autism Gene-Genome Interactions

Background: Autism spectrum disorder (ASD) has a strong genetic basis and a large number of genes have been identified that confer high risk for ASD in humans. But, it remains unknown how genetic risk translates into the phenotypic severity of ASD for a given individual.

Objectives: We hypothesize that the phenotypic severity of a heterozygous de novo autism gene mutation can be altered/modified by second site, heterozygous loss of function mutations in the genetic background of an individual.

Methods: To test this hypothesis, we took advantage of Drosophila as a model system. First, we demonstrate that heterozygous ASD mutations do not impair baseline synaptic transmission or presynaptic homeostatic plasticity (PHP). Next, we systematically combined a heterozygous ASD mutations with heterozygous chromosomal deletions that uncover defined regions of the Drosophila genome. In each double-heterozygous combination, we assessed the expression of PHP by direct quantification of synaptic transmission, entailing more than one thousand intracellular recordings.

Results: We have screened two thirds of the Drosophila genome and identified 40 loci that impair homeostatic plasticity when combined with a heterozygous autism mutation. We selected five of these loci and tested each against four additional ASD genes; CHD2, CHD8, WDFY3 and ASH1L. Assaying this set of double heterozygous mutant combinations, we discovered that more than two-thirds of the double heterozygous combinations caused impaired homeostatic plasticity. This rate of homeostatic impairment is far greater than predicted by chance (p<0.01x10-13). RNAseq analysis of double heterozygous mutant combinations, and additional phenotypic characterization of double heterozygous mutant at the electrophysiological and ultrastructural levels will be presented.

Conclusions: We propose that impaired homeostatic plasticity could be a common pathophysiology related to the phenotypic severity of ASD caused by a rare de novo mutation in a given individual. By extension, our data may define a means by which diverse categories of ASD gene mutations could converge upon a common human phenotype.