A novel therapeutic target of treatment-resistant depression

Recently, it was reported that death from hippocampal adult neurogenesis is correlated with depression. We examined whether stimulation of sigma-1 receptor (Sig-1R) improves depressive-like behaviors and hippocampal adult neurogenesis in mice. Sig-1R is a molecular chaperone regulating calcium efflux from the neuronal endoplasmic reticulum to mitochondria. Repeat treatment with dehydroepiandrosterone (DHEA), an endogeneous Sig-1R ligand, significantly ameliorated hippocampal adult neurogenesis and depressive-like behaviors in olfactory bulbectomized mice. Next, we focused on CaMKIV null mice exhibiting depressive-like behaviors and impaired adult neurogenesis. Repeated stimulation of Sig-1R by treatment with the agonist SA4503 or SSRI fluvoxamine for 14 days improved depressive-like behaviors and hippocampal adult neurogenesis in CaMKIV null mice. By contrast, treatment with paroxetine, which lacks affinity for Sig-1R, did not alter these behaviors or hippocampal adult neurogenesis. Taken together, Sig-IR stimulation increased hippocampal adult neurogenesis, which is closely associated with the therapeutic target of treatment-resistant depression.