THE 3Q29 DELETION AS A MODEL TO UNDERSTAND MOLECULAR AND CELLULAR MECHANISMS RELEVANT TO SCHIZOPHRENIA

The 3q29 deletion confers a 40-fold increased risk for schizophrenia (SZ). This high risk renders the 3q29 deletion an ideal variant for investigating molecular and cellular changes that contribute to SZ pathology. We performed a cross-species single cell RNASeq experiment using isocortex from our 3q29 deletion mouse model as well as cortical organoids created from human iPSCs. In excitatory neurons, we identified 176 genes differentially expressed in both human and mouse samples, in the same direction (up- or down-regulated in both human and mouse). These genes implicated pathways related to mitochondrial function and neurogenesis. Functional assays revealed a unique signature of mitochondrial dysfunction. Specifically, there are changes in oxygen consumption of 3q29 deletion cells, indicating an over-reliance on oxidative phosphorylation for energy production, and a phenotype of reduced metabolic flexibility. In unpublished data we have also identified alterations in the timing of cortical neurogenesis, with a time-locked wave of excess deep-layer excitatory neuron proliferation. As metabolic reprogramming is required for neuronal maturation, we now favor a model where a premature transition from glycolysis to oxidative phosphorylation may be driving altered timing of neurogenesis. Our findings dovetail with genetic pathways that have been implicated by GWAS results in idiopathic schizophrenia. These data highlight the convergence of common and rare genetic results, and showcase how genetic findings can be translated into molecular and cellular risk mechanisms for neuropsychiatric disease.