Activation of Transient Receptor Potential Vanilloid 4 Impairs Neurogenesis and Synaptic Function in the Dentate Gyrus of Adult Mice

Adult hippocampal neurogenesis in the dentate gyrus (DG) is essential for maintaining normal hippocampal function. Although activation of transient receptor potential vanilloid 4 (TRPV4) has been reported to regulate neural stem cell proliferation and dendritic development, its long-term effects on the survival of newborn neurons and hippocampal function remain unclear. Here, chronic activation of TRPV4 with the agonist GSK1016790A markedly reduced the numbers of 28-day-old BrdU⁺ and BrdU⁺/NeuN⁺ cells in the DG of adult male ICR mice (GSK mice), accompanied by decreased NeuN protein levels, indicating impaired survival of mature newborn neurons. In addition, 28-day-old BrdU⁺/NeuN⁺ neurons exhibited an altered spatial distribution in GSK mice, with an increased proportion retained within the subgranular zone and a corresponding reduction in the outer granule cell layer. Chronic TRPV4 activation also impaired long-term potentiation, reduced dendritic spine density, and decreased the expression of NR1, NR2A, NR2B, postsynaptic density protein 95 (PSD95), and synaptophysin. These alterations were accompanied by reduced activation of the Ras-Raf1-MEK-ERK1/2-CREB, PI3K-Akt-GSK3β-CREB, and PI3K-Akt-mTOR signaling pathways. Notably, pharmacological activation of PI3K or ERK restored the survival and altered spatial distribution of newborn neurons, dendritic spine density, synaptic protein expression, synaptic plasticity, and spatial learning and memory performance in GSK mice. Collectively, these findings demonstrate that chronic TRPV4 activation disrupts adult hippocampal neurogenesis, synaptic function, and cognition. These pathological changes were associated with reduced activation of ERK- and PI3K-related signaling pathways, suggesting that the downregulation of these pathways may contribute to the detrimental effects of chronic TRPV4 activation on hippocampal function. TRPV4 Activation Impairs Neurogenesis, Synaptic Function, and Cognition Activation of TRPV4 impairs adult hippocampal neurogenesis, synaptic structure and function, ultimately contributing to cognitive impairment. These alterations are associated with the downregulation of the PI3K-Akt and Ras-Raf1-MEK-ERK1/2 signaling pathways