The IKC-leptin axis functions as a molecular bridge between neurodevelopment and endocrine signaling

Kcnb1, a voltage-gated K⁺ channel widely expressed in brain, assembles with integrins to form integrin-K⁺ channel complexes (IKCs) in cortex and hypothalamus. Pathogenic KCNB1 variants cause Developmental and Epileptic Encephalopathy (DEE), and Kcnb1-null (Null) mice reproduce core neurodevelopmental defects alongside chronic hypoleptinemia, suggesting a leptin-IKC signaling axis. We find that Kcnb1, integrins, and the leptin receptor (LepR) co-immunoprecipitate and co-localize in cortical neurons. Perinatal leptin supplementation in Null mice improves cognition, corrects cortical anatomy, and restores neuronal migration, dendritic arborization, and synaptic functionality. In primary Null cortical neurons, leptin normalizes dendritic growth and actin remodeling via integrin-dependent mechanisms. By contrast, leptin has modest effects in WT animals and neurons; sensitivity is unmasked by pharmacological manipulation of integrins, and, strikingly, LepR blockade in the absence of exogenous leptin is sufficient to induce Null-like defects in WT neurons. These findings argue that hypoleptinemia alone does not drive the Null phenotype. Instead, they reveal a previously unrecognized, dual-mode model in which LepR signaling is regulated by both its ligand and IKCs. This conceptual advance links IKC-LepR coupling to neurodevelopment and DEE and pinpoints their interface as a tractable therapeutic target.