How do changes in gene dosage affect circuit wiring that can lead to neuropsychiatric disorders? How can we better model polygenic diseases like schizophrenia?

Most neuropsychiatric disorders are polygenic and have many different combinations of causal mutations. Many single nucleotide polymorphisms (SNPs) in recent genome-wide association studies (GWAS) for neuropsychiatric disorders are found in regulatory regions of genes. These SNPs are more likely to affect transcriptional regulation instead of producing gain-of-function or loss-of-function mutations in the protein coding region. Additionally, many risk-genes are up- or down-regulated in specific regions of the brain in human post-mortem tissue.

With this in mind, my goal is to create a method to affect transcriptional regulation of multiple neuropsychiatric risk-genes to better model human disease genetics. Using CRISPR activation/interference (CRISPRa/i) and in utero electroporation (IUE), I can up- and down-regulate risk-genes in the developing rodent cortex and investigate how this can affect circuit wiring. I then plan to multiplex this method to change gene dosage of several genes in the same cells in vivo. 

In the future, I plan to bring this technique to non-human primates, like marmosets, to get a better understanding of human disease genetics.