title: Sex-related neurogenesis decrease in hippocampal dentate gyrus with depressive-like behaviors in sigma-1 receptor knockout mice.
abstract: 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.
authors.affiliation: State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China; Department of Physiology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Sha
authors.initials: S
authors.lastname: Sha
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Hong
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Wei-Jun
authors.initials: WJ
authors.lastname: Qu
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Zi-Hong
authors.initials: ZH
authors.lastname: Lu
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: The Key Lab of Molecular Biology, Guiyang Medical University, Guiyang 550004, Guizhou, China.
authors.forename: Wen-Feng
authors.initials: WF
authors.lastname: Yu
authors.affiliation: State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China; Department of Physiology, Nanjing Medical University, Nanjing 210029, China. Electronic address: lingchen@njmu.edu.cn.
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
mesh_terms: D000818:Animals; D018891:Dentate Gyrus / Q000187:drug effects / Q000502:physiology*; D003863:Depression / Q000503:physiopathology*; D004031:Diestrus / Q000502:physiology; D004958:Estradiol / Q000097:blood; D005260:Female; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D018345:Mice, Knockout; D016202:N-Methylaspartate / Q000378:metabolism; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010052:Ovariectomy; D011359:Proestrus / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D017480:Receptors, sigma / Q000235:genetics / Q000378:metabolism*; D012727:Sex Characteristics; D000097605:Sigma-1 Receptor
chemical_list: D004958:Estradiol; D016202:N-Methylaspartate; D016194:Receptors, N-Methyl-D-Aspartate; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C121001:NR2B NMDA receptor
keywords: Depression; Estradiol (E2); N-methyl-d-aspartate receptor (NMDAr); Neurogenesis; Sigma-1 receptor (σ(1)R)