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Sex-related neurogenesis decrease in hippocampal dentate gyrus with depressive-like behaviors in sigma-1 receptor
Sha Sha1, Juan Hong2, Wei-Jun Qu2
1State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China; Department of Physiology, Nanjing Medical University, Nanjing 210029, China.
Summary
Sigma-1 receptor deficiency causes depression-like behaviors and reduced neurogenesis in male mice. Estradiol (E2) treatment rescues these deficits by modulating NMDA receptor activity and neuroprotection.
Area of Science:
- Neuroscience
- Endocrinology
- Pharmacology
Background:
- Sigma-1 receptor (σ1R) knockout mice exhibit sex-specific depressive-like phenotypes.
- Neurogenesis in the hippocampal dentate gyrus (DG) is crucial for cognitive function and mood regulation.
Purpose of the Study:
- To investigate the role of σ1R deficiency in depressive-like behaviors and neurogenesis.
- To elucidate the sex-dependent effects of estradiol (E2) and its underlying mechanisms involving NMDA receptors (NMDAr) and Src signaling.
Main Methods:
- Utilized male and female σ1R knockout (σ1R(-/-)) and wild-type (WT) mice, including ovariectomized (OVX) models.
- Administered E2, NMDAr agonists, and inhibitors of Src and NR2B.
- Assessed depressive-like behaviors, hippocampal neurogenesis, NMDA-activated current (INMDA), and protein phosphorylation (Src, NR2B).
Main Results:
- Male σ1R(-/-) mice displayed depressive-like behaviors and reduced DG neurogenesis, which were rescued by E2 treatment.
- E2 normalized INMDA and NR2B phosphorylation in male σ1R(-/-) mice, mediated by Src.
- Female σ1R(-/-) mice, particularly after E2 deprivation or Src inhibition, exhibited deficits similar to males, indicating a protective role of endogenous E2.
Conclusions:
- σ1R deficiency impairs neurogenesis and induces depressive-like phenotypes, particularly in males.
- Estradiol exerts neuroprotective and antidepressant effects in σ1R-deficient mice by modulating NMDAr and Src signaling pathways.
- These findings highlight the critical interplay between σ1R, E2, and NMDAr in regulating mood and neurogenesis.
