Unraveling the role of NALCN in neural circuit development

The sodium (Na+)-leak channel (NALCN) maintains neuronal resting membrane potential by conducting a sodium leak current. Pathogenic mutations in the NALCN channelosome complex (NALCN-UNC80-UNC79) are linked to rare developmental and epileptic encephalopathies. However, despite the prevalence of cognitive deficits in NALCN-related disorders, the precise role of NALCN in brain development remains elusive. To address this gap, we investigated the contribution of Nalcn to cortical neural circuit formation using mouse models. Employing Nalcn-GFP reporter mice in conjunction with immunohistochemistry and electron microscopy, we mapped Nalcn expression in cortical glutamatergic and GABAergic neurons, revealing specific enrichment across different subcellular compartments in subtypes of these neurons. In addition, a neuroanatomical and molecular characterization of mouse models with Nalcn loss- and gain-of-function during corticogenesis revealed Nalcn's necessity for the generation of normal density of deep layer pyramidal neurons. Moreover, behavioral assessments of NALCN dysfunction models unveiled sex-specific deficits upon Nalcn deletion in cortical glutamatergic neurons. In conclusion, our study sheds light on the critical role of Nalcn in regulating the development of cortical glutamatergic neurons, providing insights into pathophysiological mechanisms associated to channelopathies of NALCN. Our findings significantly contribute to a better understanding of NALCN's function in cortical circuit formation and highlight its potential as therapeutic target during critical periods of cortical glutamatergic circuit development.