IKKβ inhibits cognitive memory and adult hippocampal neurogenesis by modulating the β-catenin pathway.

Aim: The IKKβ signaling pathway regulates NF-κB, influencing inflammation and cell survival in the brain. Radial glia cells are crucial for hippocampal neurogenesis and cognition. However, the role and mechanisms of IKKβ in modulating radial glia behavior and its impact on memory and neurogenesis remain unclear. Further studies are needed to understand how alterations in this pathway affect hippocampal function.

Main Methods: The role of IKKβ in memory and hippocampal neurogenesis was examined using GFAP-CreERT2/IKKβ mice with IKKβ knockdown in radial glia cells. IKKβ expression, NSC proliferation, and differentiation were assessed by immunohistochemistry. NF-κB and β-catenin interactions were evaluated by immunoprecipitation. Cultured adult hippocampal NSCs, with IKKβ or β-catenin shRNA transfection, were analyzed by flow cytometry and western blot to examine stem cell characteristics, NF-κB signaling, cell cycle, and β-catenin pathways.

Key Findings: Our results showed IKKβ cKD increased exploratory activity in the open-field and hyperactivity in the Y-maze, as well as enhanced spatial memory in the object location and Morris water maze tests. It also promoted adult hippocampal NSC proliferation by upregulating positive and inhibiting negative cell cycle regulators. Neuronal differentiation was enhanced, affecting β-catenin signaling and NeuroD1 expression. Additionally, IKKβ cKD promoted NSC survival, as shown by decreased cleaved caspase-3 and reduced Bax and cytochrome c in the hippocampus.

Significance: These findings suggest that in hippocampal NSCs, IKKβ inhibits locomotion, cognitive function, and adult hippocampal neurogenesis by suppressing the β-catenin signaling, highlighting its key role in decreasing hippocampal neurogenesis and cognitive function through NF-κB signaling in adult NSCs.