Ion channels in neurodevelopment: lessons from the Integrin-KCNB1 channel complex

Ion channels modulate cellular excitability by regulating ionic fluxes across biological membranes. Pathogenic mutations in ion channel genes give rise to epileptic disorders that are among the most frequent neurological diseases affecting millions of individuals worldwide. Epilepsies are triggered by an imbalance between excitatory and inhibitory conductances. However, pathogenic mutations in the same allele can give rise to loss-of-function and/or gain-of-function variants, all able to trigger epilepsy. Furthermore, certain alleles are associated with brain malformations even in the absence of a clear electrical phenotype. This body of evidence argues that the underlying epileptogenic mechanisms of ion channels are more diverse than originally thought. Studies focusing on ion channels in prenatal cortical development have shed light on this apparent paradox. The picture that emerges is that ion channels play crucial roles in landmark neurodevelopmental processes, including neuronal migration, neurite outgrowth, and synapse formation. Thus, pathogenic channel mutants can not only cause epileptic disorders by altering excitability, but further, by inducing morphological and synaptic abnormalities that are initiated during neocortex formation and may persist into the adult brain.