Computational Modeling of Genetic Contributions to Excitability and Neural Coding in Layer V Pyramidal Cells: Applications to Schizophrenia Pathology.

Abstract

Pyramidal cells in layer V of the neocortex are one of the most widely studied neuron types in the mammalian brain. Due to their role as integrators of feedforward and cortical feedback inputs, they are well-positioned to contribute to the symptoms and pathology in mental disorders—such as schizophrenia—that are characterized by a mismatch between the internal perception and external inputs. In this modeling study, we analyze the input/output properties of layer V pyramidal cells and their sensitivity to modeled genetic variants in schizophrenia-associated genes. We show that the excitability of layer V pyramidal cells and the way they integrate inputs in space and time are altered by many types of variants in ion-channel and Ca2+ transporter-encoding genes that have been identified as risk genes by recent genome-wide association studies. We also show that the variability in the output patterns of spiking and Ca2+ transients in layer V pyramidal cells is altered by these model variants. Importantly, we show that many of the predicted effects are robust to noise and qualitatively similar across different computational models of layer V pyramidal cells. Our modeling framework reveals several aspects of single-neuron excitability that can be linked to known schizophrenia-related phenotypes and existing hypotheses on disease mechanisms. In particular, our models predict that single-cell steady-state firing rate is positively correlated with the coding capacity of the neuron and negatively correlated with the amplitude of a prepulse-mediated adaptation and sensitivity to coincidence of stimuli in the apical dendrite and the perisomatic region of a layer V pyramidal cell. These results help to uncover the voltage-gated ion-channel and Ca2+ transporter-associated genetic underpinnings of schizophrenia phenotypes and biomarkers.