Computational modelling of schizophrenia-associated alterations of ion-channel-encoding gene expression predicts a...

Schizophrenia presents with a wide range of phenotypes that can help to understand the the mechanisms of the disease. Among these, alterations in delta oscillations are especially amenable to experimental investigation, yet the mechanisms underlying these changes remain insufficiently understood. Biophysically detailed computational modeling offers a powerful approach to investigate these phenomena, as it enables multi-scale integration of genetic and electrophysiological data. In this study, we developed a minimal network model composed of biophysically detailed, multicompartmental neurons to replicate experimental data on the effects of pharmacological blockage of gabaergic neurotransmission on delta-band power. We inserted post-mortem RNA expression data from the anterior cingulate and prefrontal cortices of individuals with schizophrenia and matched controls into the model to study the effects of schizophrenia-associated alterations of ion-channel expression on delta-oscillation power. Our simulations revealed a significant reduction in delta-band power in schizophrenia, driven by altered expression of calcium channel genes in pyramidal neurons. These results provide insights into the genetic contributions to oscillatory disruptions observed in schizophrenia, and our modelling framework can help to develop stratification strategies that bridge genetics and in vivo electrophysiology.