Sex-related neurogenesis decrease in hippocampal dentate gyrus with depressive-like behaviors in sigma-1 receptor knockout mice

Male sigma-1 receptor knockout (σ1R−/−) mice showed depressive-like phenotype with deficit in the survival of newly generated neuronal cells in the hippocampal dentate gyrus (DG), but female σ1R−/− mice did not. The level of serum estradiol (E2) at proestrus or diestrus did not differ between female σ1R−/− mice and wild-type (WT) mice. Ovariectomized (OVX) female σ1R−/− mice, but not WT mice, presented the same depressive-like behaviors and neurogenesis decrease as male σ1R−/− mice. Treatment of male σ1R−/− mice with E2 could alleviate the depressive-like behaviors and rescue the neurogenesis decrease. In addition, E2 could correct the decline in the density of NMDA-activated current (INMDA) in granular cells of DG and the phosphorylation of NMDA receptor (NMDAr) subtype 2B (NR2B) in male σ1R−/− mice, which was associated with the elevation of Src phosphorylation. The neuroprotection and antidepressant effects of E2 in male σ1R−/− mice were blocked by the inhibitor of Src or NR2B. The NMDAr agonist showed also the neuroprotection and antidepressant effects in male σ1R−/− mice, which were insensitive to the Src inhibitor. On the other hand, either the deprivation of E2 or the inhibition of Src in female σ1R−/− mice rather than WT mice led to a distinct decline in INMDA and NR2B phosphorylation. Similarly, the Src inhibitor could cause neurogenesis decrease and depressive-like behaviors in female σ1R−/− mice, but not in WT mice. These results indicate that the σ1R deficiency impairs neurogenesis leading to a depressive-like phenotype, which is alleviated by the neuroprotection of E2.