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

Kcnb1-null mice exhibit hypoleptinemia, disrupted Kcnb1-integrin-K+ channel complex (IKC) interactions with the leptin receptor (LepR) in proopiomelanocortin neurons, and broad neurodevelopmental and cognitive abnormalities. Because leptin is neurotrophic and IKC-LepR assemblies are present in neocortex, we tested whether leptin modifies these phenotypes. Early-life leptin supplementation partially improved behavioral and cognitive deficits and more strongly corrected anatomical and neuronal abnormalities. In null cortical neurons, leptin normalized dendritic overgrowth and F-actin dynamics through LepR- and integrin-dependent mechanisms. WT animals and neurons showed modest leptin responses; however, integrin manipulation unmasked leptin sensitivity, whereas LepR blockade induced null-like defects without exogenous leptin. These findings support a dual-mode model in which LepR signaling is regulated by both ligand availability and IKC-dependent mechanisms, identifying IKC-LepR coupling as a molecular interface linking endocrine signaling to neocortical development.