![]() It is not coincidental that in vitro IKCs formed with certain KCNB1 DEE-variants, impair cellular functions such as migration and neuritogenesis, through non-ionic mechanisms. While the mechanisms underlying DEEs are currently under investigation, accumulating evidence points out to abnormal neuronal development and resulting synaptic connectivity disturbances, as one of the underlying causes. The crucial role of IKCs is further underscored by the fact that mutations in the KCNB1 gene are found in children affected by developmental and epileptic encephalopathies (DEEs), neurological conditions characterized by severe developmental delays, that often co-exist with seizures and abundant epileptiform abnormalities. Evidence suggests that IKCs regulate fundamental cellular functions, such as migration, proliferation, survival and death through non-conducting (non-ionic) mechanisms. The voltage-gated K + channel KCNB1, forms macromolecular complexes with integrins, named Integrin_K + channel_Complexes (IKCs). This underscores a previously unknown role of IKCs as key players in neuronal development, and implicate developmental channelopathies in the etiology of DEEs. Thus, a genetic mutation in a K + channel induces severe neuromorphological abnormalities through non-conducting mechanisms, that can be rescued by pharmacological intervention. Treatment with Angiotensin II in vitro, an agonist of Focal Adhesion kinase, a key component of IKC signaling machinery, corrected the neuronal abnormalities. Wild type (WT) and R312H KCNB1 channels made complexes with integrins α5β5 (Integrin_K + channel_Complexes, IKCs), whose biochemical signaling was impaired in R312H brains. The R312H mice exhibited a similar phenotype to the null mice. ![]() To determine whether defective KCNB1 can give rise to developmental channelopathy, we constructed Knock In (KI) mice, harboring the gene variant Kcnb1 R312H (R312H mice) found in children with developmental and epileptic encephalopathies (DEEs). Mice developed seizure phenotype, anxiety, and compulsive behavior. Migratory defects persisted into the adult brains, along with disrupted morphology and synaptic connectivity. Neuronal migration of glutamatergic neurons was impaired in the neocortices of KCNB1 null mice. Here, we investigate the role of voltage-gated K + channel KCNB1 (Kv2.1) in neocortical development. Potassium (K +) channels are robustly expressed during prenatal brain development, including in progenitor cells and migrating neurons, but their function is poorly understood.
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