Functional role of dentate gyrus calbindin-D28K in supporting neurogenesis and emotional-social behavior relevant to antidepressant action

Calbindin-D28K (Calb1) is a calcium-binding protein that regulates intracellular calcium signaling and neuronal excitability. In the hippocampal dentate gyrus (DG), Calb1 expression increases with granule cell maturation but is downregulated following chronic antidepressant treatment. To elucidate the functional relevance of this antidepressant-associated downregulation, we used an adeno-associated virus-mediated knockdown approach in mice to reduce Calb1 expression in the DG. Calb1 knockdown significantly reduced the expression of FosB, an activity-dependent marker, under basal conditions and impaired neurogenesis by suppressing neural stem/progenitor cell proliferation and delaying neuronal maturation. Behavioral analyses revealed that Calb1 knockdown mice displayed heightened anxiety-associated behavior and reduced social interaction, whereas locomotor activity remained unaffected. These findings suggest that Calb1 expression in the DG supports basal activity-dependent responses, adult neurogenesis and emotional-social behavior. Paradoxically, while chronic antidepressant treatment reduces Calb1 expression, our results indicate that maintaining Calb1 may be essential for sustaining neurogenesis and proper emotional regulation. This discrepancy highlights the complexity of antidepressant mechanisms and suggests that Calb1 is a key regulator for enhancing hippocampal function and behavioral adaptation.