Activation of transient receptor potential vanilloid 4 impairs long-term depression in nucleus accumbens and induces depressive-like behavior.

Long-term depression (LTD), a form of synaptic plasticity, is impaired in the nucleus accumbens (NAc) in depression. While TRPV4 activation regulates synaptic transmission in the hippocampus, its effects in the NAc remain unclear. Here, we examined the effects of TRPV4 activation on LTD induction in the NAc and depressive-like behavior. Mice that were administered the TRPV4 agonist GSK1016790A into the NAc (GSK-mice) showed depressive-like behavior and impaired LTD induction in NAc slices. Additionally, the mRNA and protein levels of dopamine D2 receptor (D2R) and A-type gamma-aminobutyric acid receptor (GABAAR) were markedly decreased in the NAc of GSK-mice. Meanwhile, administering a D2R (quinpirole) or GABAAR (muscimol) agonist reversed LTD impairment in the NAc. The protein levels of phosphorylated protein kinase C (p-PKC) increased markedly and that of phosphorylated protein kinase B (p-Akt) decreased in the NAc of GSK mice. Administration of a PKC antagonist (GF109203X) or phosphatidylinositol 3-kinase (PI3K) agonist (740 Y-P) significantly increased GABAAR protein levels and restored LTD induction in the NAc of GSK-mice. Administration of quinpirole increased p-Akt and GABAAR protein levels in the NAc of GSK-mice. Finally, administration of quinpirole, muscimol, GF109203X or 740 Y-P improved the depressive-like behavior in GSK-mice. This study suggests that activation of TRPV4 impairs LTD induction in the NAc and induces depressive-like behavior, which is likely mediated by down-regulating D2R to inhibit PI3K-Akt pathway, and activating PKC to decrease the expression of GABAAR.