Investigating interneuron development in Autism

Project Code: 2020-SIDB-06

Recent genetic efforts have identified large numbers of mutations as risk factors for Autism, frequently in association with other neuropsychiatric conditions including intellectual disability and epilepsy. A central question in Autism genetics is how such a variety of genes with a broad range of cell and molecular functions converge on the Autistic phenotype. We have used bioinformatic analysis to identify classes of cells, notably cells destined to become interneurons, in developing human cerebral cortex that are likely to be particularly vulnerable to a large number of Autism-causing mutations (Mi et al., 2018; Zhong et al., 2018) & unpublished data from Pratt lab. This result gives extremely strong motivation for obtaining a deeper understanding of these interneurons, the effect that Autism causing mutations have on interneuron development, and when. The proper functioning of the mature cerebral cortex depends on the balance between excitatory pyramidal neurons (originating from progenitors located in the ventricular zone of the cerebral cortex) and inhibitory interneurons (originating from progenitors located in the ganglionic eminences) that migrate to the cortex and integrate into functional circuits with pyramidal neurons in the cortical plate. This E/I balance is particularly important for normal brain function and disruption to this balance is thought to underpin Autism (Nelson and Valakh, 2015). The overarching goal of this project is to test the hypothesis that Autism causing mutations target interneuron development producing interneuron cell and molecular phenotypes contributing to Autistic brain function. Specifically, this project will make use of human and/or rodent models to characterise the vulnerable interneurons in more depth using markers identified by our bioinformatics analysis, study the expression of Autism-linked genes in these interneurons to refine hypotheses about the stage(s) of their developmental trajectory affected by Autism causing mutations, and then test these hypotheses by investigating how manipulating Autism-linked genes perturbs interneuron development.