Role of endogenous NT-3 in neuronal activity and neurogenesis in the hippocampal dentate gyrus

Neurotrophin-3 (NT-3) is a neurotrophic factor that regulates neuronal differentiation and synaptic plasticity. In the adult central nervous system, NT-3 is predominantly expressed in the hippocampal dentate gyrus (DG). Chronic antidepressant treatment suppresses Ntf3 expression in the DG; however, its functional significance remains unclear. To investigate the role of NT-3 in the adult DG, an adeno-associated virus (AAV)-mediated knockdown system was employed in mice. Immunohistochemical analysis revealed that TrkC, the high-affinity receptor for NT-3, was highly expressed in the DG. Under basal conditions, NT-3 knockdown significantly reduced the expression of FosB, an activity-dependent marker. Gene expression analysis showed that Arc, Egr1, and Fosb expressions were also significantly decreased. Although NT-3 knockdown did not affect cell proliferation in the DG, it impaired dendritic elongation in immature neurons. Additionally, NT-3 knockdown significantly reduced Npy expression. These findings suggest that endogenous NT-3 in the adult DG regulates both basal neuronal activity and newborn neuronal differentiation, contributing to hippocampal homeostasis. Further research is required to determine whether NT-3 downregulation induced by chronic antidepressant treatment influences neuronal activity and hippocampal plasticity in neuropsychiatric conditions.