Integrin-KCNB1 potassium channel complexes regulate neocortical neuronal development and are implicated in epilepsy

Alessandro Bortolami, Wei Yu, Elena Forzisi, Koray Ercan, Ritik Kadakia, Madhuvika Murugan, Denise Fedele, Irving Estevez, Detlev Boison, Mladen Roko Rasin, Federico Sesti

Research output: Contribution to journalArticlepeer-review

Abstract

Potassium (K+) channels are robustly expressed during prenatal brain development, including in progenitor cells and migrating neurons, but their function is poorly understood. Here, we investigate the role of voltage-gated K+ channel KCNB1 (Kv2.1) in neocortical development. Neuronal migration of glutamatergic neurons was impaired in the neocortices of KCNB1 null mice. Migratory defects persisted into the adult brains, along with disrupted morphology and synaptic connectivity. Mice developed seizure phenotype, anxiety, and compulsive behavior. To determine whether defective KCNB1 can give rise to developmental channelopathy, we constructed Knock In (KI) mice, harboring the gene variant Kcnb1R312H (R312H mice) found in children with developmental and epileptic encephalopathies (DEEs). The R312H mice exhibited a similar phenotype to the null mice. 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. Treatment with Angiotensin II in vitro, an agonist of Focal Adhesion kinase, a key component of IKC signaling machinery, corrected the neuronal abnormalities. Thus, a genetic mutation in a K+ channel induces severe neuromorphological abnormalities through non-conducting mechanisms, that can be rescued by pharmacological intervention. This underscores a previously unknown role of IKCs as key players in neuronal development, and implicate developmental channelopathies in the etiology of DEEs.

Original languageEnglish (US)
JournalCell Death and Differentiation
DOIs
StateAccepted/In press - 2022

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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