Excitatory neuron-specific core binding factor β (Cbfβ) deletion causes sex-independent spatial memory deficits and female-specific anxiety and depression-like behaviors in mice

Core-binding factor subunit β (Cbfβ) serves as a transcriptional cofactor for the Runx transcription factors, with well-established roles in hematopoiesis and skeletal development. However, its function within the central nervous system (CNS) remains largely unexplored. To investigate the role of Cbfβ in the brain, we generated neuron-specific Cbfβ knockout mice (Cbfb^br/br) using the Emx1-Cre system. Behavioral assessments included the Y-maze test for short-term spatial memory, the open field test, and the elevated plus maze (EPM) for anxiety-like behaviors. Depression-like behaviors were evaluated following chronic restraint stress (CRS) using the EPM and tail suspension test. Hippocampus and cortex protein levels of Cbfβ, Runx1, Runx2, Runx3, and Doublecortin (DCX) were quantified using Western blotting, and BDNF mRNA expression was measured using quantitative real-time PCR. Cbfβ deletion in excitatory neurons led to significant short-term spatial memory deficits in both sexes. Female Cbfb^br/br mice exhibited elevated anxiety-like behaviors and heightened depression-like responses following CRS. Western blot analysis revealed reduced Runx1 and Runx2 protein levels in the hippocampus and cortex of both sexes, while Runx3 remained unchanged. BDNF mRNA expression was significantly downregulated in Cbfb^br/br mice of both sexes. Notably, DCX protein levels were selectively decreased in females, indicating a sex-specific effect on neurogenesis. Excitatory neuron-specific deletion of Cbfβ impairs spatial memory and induces female-specific emotional disturbances, linked to reduced hippocampal expression of Runx1, Runx2, BDNF, and DCX. These findings identify Cbfβ as a critical regulator of hippocampal function and a potential target for sex-specific research into mood and cognitive disorders.