IKKβ inhibits cognitive memory and adult hippocampal neurogenesis via the β-catenin pathway

Abstract

The role of IκB kinase β (IKKβ) and its underlying mechanism in regulating cognitive memory and hippocampal neurogenesis were investigated using GFAP-CreERT2/IKKβflox/flox transgenic mice, where the IKKβ gene is specifically knocked down in hippocampal neural stem cells (NSCs) to generate IKKβ conditional knockdown (cKD) mice. Our findings indicate that IKKβ cKD led to increased exploratory activity in the open-field test, promoted hyperactivity in the Y-maze test, and enhanced spatial learning and memory function in the object location and the Morris water maze tests. Furthermore, IKKβ cKD increased the proliferation of adult hippocampal NSCs by upregulating positive cell cycle regulators through the inhibition of negative cell cycle regulators. Neuronal differentiation of adult hippocampal NSCs was also increased by IKKβ cKD, affecting β-catenin signaling and Neurogenic differentiation 1. Additionally, IKKβ cKD enhanced NSC survival, as indicated by decreased cleaved caspase-3 levels and diminished Bax and Cytochrome c expression in the hippocampal dentate gyrus. These findings indicate that in hippocampal NSCs, IKKβ inhibits locomotion, cognitive function, and adult hippocampal neurogenesis by suppressing the β-catenin signaling pathway. Our findings highlight a key role for IKKβ in the inhibition of cognitive function and decrease in hippocampal neurogenesis through NF-κB signaling in adult NSCs.