Loss of schizophrenia risk gene XPO7 disrupts neuronal excitability and network regularity via altered Na+ channel dynamics in human neurons

Schizophrenia is a highly heritable psychiatric disorder, yet the molecular mechanisms by which genetic risk contributes to disease pathophysiology remain largely unknown. In this study, we investigate the functional consequences of XPO7 loss of function (LoF) in human induced pluripotent stem cell (iPSC)-derived neurons, focusing on its role as a schizophrenia risk gene identified through recent large-scale exome sequencing analyses. By integrating high-precision electrophysiological measurements with transcriptomic, proteomic, and imaging approaches, we demonstrate that XPO7 LoF alters Na+ channel properties and availability, disrupts neuronal excitability, and impairs the synchrony and regularity of network activity. These functional deficits are accompanied by widespread molecular dysregulation affecting nucleocytoplasmic transport, ion channel function, and synaptic composition. Among the dysregulated proteins is Nav1.2, a voltage-gated sodium channel encoded by the schizophrenia-associated gene SCN2A, which exhibits aberrant subcellular distribution in XPO7 LoF neurons, characterized by increased somatic accumulation and reduced synaptic localization. Together, these findings position XPO7 as a critical regulator of neuronal excitability and connectivity, linking channelopathy to cellular phenotypes relevant to schizophrenia pathophysiology.