Caveolin-1 Regulates Neurogenesis and Learning and Memory by Modulation of Mitochondrial Dynamics

Hippocampal neurogenesis plays instrumental roles in learning and memory. However, the mechanisms underlying neurogenesis are not fully understood. Here we show that the expression of Caveolin-1 (Cav-1), the principal component of caveolae, peaks in neural progenitor cells (NPCs) during neurogenesis. Using NestinCreERT2;Cav-1fl/fl male mice, and CRISPR-sham (Cav-1 Ctrl) and CRISPR/Cas9-edited (Cav-1 KO) human induced-pluripotent stem cells, we observed that Cav-1 deletion led to reduced stem cell proliferation and enhanced differentiation into neurons. This was manifested by increased neuronal dendritic tree surface area and enhanced mouse performance in contextual discrimination. Proteomic analysis revealed that Cav-1 plays a role in mitochondrial pathways in NPCs. Cav-1 localized to the mitochondria in NPCs and co-immunoprecipitated with mitofusion 2. Mitochondrial morphology was elongated in Cav-1 KO NPCs and the expression of mitofusion 2 was increased in mitochondrial fractions. Restoration of Cav-1 levels rescued elongated mitochondrial morphology and altered neuronal differentiation in Cav-1 KO NPCs. Together, this study identifies Cav-1 as a novel regulator of neurogenesis and -dependent learning and memory. Significance StatementThe hippocampal dentate gyrus (DG) orchestrates adult hippocampal neurogenesis (AHN). The precise mechanisms governing AHN remain elusive. Caveolin-1 regulates neurogenesis through mitochondrial fission-fusion process, suggesting Caveolin-1 as a novel regulator of AHN and underscoring the impact of AHN on cognition.