Studying human neuropsychiatric disease in DLG2 deficient neurons

Neuropsychiatric diseases such as schizophrenia can have profound impacts both on affected individuals and society more widely yet the neurobiology underlying these conditions is incompletely understood. Various environmental and genetic risk factors have been identified for these diseases which include rare deletions of the DLG2 gene, identified in multiple schizophrenia patients. DLG2 is known to encode a structural scaffolding protein within mature synapses; however, research presented here indicates protein expression earlier than previously appreciated and prior to synaptogenesis. To investigate a hypothesised role for DLG2 in early cortical neurogenesis and determine potential disease relevance, DLG2-/- and isogenic wild-type (WT) sister human embryonic stem cell (hESC) lines were differentiated into cortical excitatory neurons and characterised at multiple time points through various techniques, including RNA sequencing. These revealed novel roles for DLG2 during cortical development including the regulation of neural precursor cell (NPC) proliferation and adhesion to the extracellular matrix (ECM) as well as several biological progresses during neurogenesis responsible for the generation of neuronal subtype identity. DLG2-/- cultures produce more immature neurons characterised by deficits in morphology, migration, electrical properties and gene expression, including the cortical layer V marker CTIP2. Genes downregulated at day 30 of cortical differentiation, a time point corresponding to early neurogenesis, were enriched for schizophrenia common risk variants, linking DLG2 regulated biological processes in corticoneurogenesis with neuropsychiatric disease and potentially providing insight into the neurodevelopmental component of schizophrenia pathophysiology