Sigma‐1 Receptor Knockout Impairs Neurogenesis in Dentate Gyrus of Adult Hippocampus <i>Via</i> Down‐Regulation of <scp>NMDA</scp> Receptors

Sha, Sha; Qu, Wei-Jun; Li, Lin; Lu, Zihong; Chen, Lei; Yu, Wenbin; Chen, Ling

doi:10.1111/cns.12129

Cited by 58 publications

(51 citation statements)

References 56 publications

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“…Thus, the lack of an anti-depressive effect by paroxetine in CaMKIV null mice suggests that Sig-1R stimulatory action rather than serotonin reuptake inhibition accounts for fluvaxamine's anti-depressive action. However, lack of amelioration by fluoxetine as reported by Sha et al [44] cannot be explained due to a low affinity for Sig-1R. Our hypothesis that fluvoxamine-induced anti-depressive action in CaMKIV null mice is mediated by Sig-1R stimulation was confirmed by the observation that the Sig-1R-specific agonist SA4503 ameliorates impaired adult hippocampal neurogenesis in DG and depressive behaviors in CaMKIV null mice.…”

Section: Discussionsupporting

confidence: 82%

“…In fact, the elevation of CaMKII activity by SA4503 was eliminated by NMDAR antagonist. The regulation of NMDAR activity by Sig-1R was also reported in Sig-1R null mice in which adult hippocampal neurogenesis is impaired via downregulation of NMDAR subunit NR2B [44]. Martina et al [54] reported that a Sig-1R agonist inhibits small-conductance calcium-activated potassium channel in the hippocampus and consequently increased Ca 2+ mobilization by an NMDAR-dependent mechanism.…”

Section: Discussionmentioning

confidence: 83%

“…Since impaired adult hippocampal neurogenesis in DG correlates with depressive-like behaviors in OBX mice [7,8] and Sig-1R null mice showed impaired adult hippocampal neurogenesis in DG [44], we hypothesized that depressivelike behaviors in CaMKIV null mice are associated with lost or impaired Sig-1R function in hippocampal DG and that paroxetine-resistant depression may be improved by treatment with Sig-1R agonists.…”

Section: Discussionmentioning

confidence: 99%

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Stimulation of Sigma-1 Receptor Ameliorates Depressive-like Behaviors in CaMKIV Null Mice

et al. 2014

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Sigma-1 receptor (Sig-1R) is a molecular chaperone regulating calcium efflux from the neuronal endoplasmic reticulum to the mitochondria. Calcium/calmodulin-dependent protein kinase IV (CaMKIV) null mice exhibit depressive-like behaviors and impaired neurogenesis as assessed by bromodeoxyuridine (BrdU) incorporation into newborn cells of the hippocampal dentate gyrus (DG). Here, we demonstrate that chronic stimulation of Sig-1R by treatment with the agonist SA4503 or the SSRI fluvoxamine for 14 days improves depressive-like behaviors in CaMKIV null mice. By contrast, treatment with paroxetine, which lacks affinity for Sig-1R, did not alter these behaviors. Reduced numbers of BrdU-positive cells and decreased brain-derived neurotrophic factor (BDNF) mRNA expression and protein kinase B (Akt; Ser-473) phosphorylation seen in the DG of CaMKIV null mice were significantly rescued by chronic Sig-1R stimulation. Interestingly, reduced ATP production observed in the DG of CaMKIV null mice was improved by chronic Sig-1R stimulation. Such stimulation also improved hippocampal long-term potentiation (LTP) induction and maintenance, which are impaired in the DG of CaMKIV null mice. LTP rescue was closely associated with both increases in calcium/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation and GluA1 (Ser-831) phosphorylation. Taken together, Sig-1R stimulation by SA4503 or fluvoxamine treatment increased hippocampal neurogenesis, which is closely associated with amelioration of depressive-like behaviors in CaMKIV null mice.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

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Stimulation of Sigma-1 Receptor Ameliorates Depressive-like Behaviors in CaMKIV Null Mice

et al. 2014

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“…An earlier study (Yang et al, 2011) reported that σ 1 R agonist enhances the survival of newborn neurons in an NMDArdependent manner. The σ 1 R deficiency suppresses the NR2B phosphorylation leading to the dysfunction of NMDAr without the changes in membrane properties, which impairs the survival of newborn neurons in the DG (Sha et al, 2013). The density of NMDAr is lower in the brain of depressed patients compared to controls (Nudmamud-Thanoi and Reynolds, 2004;Nowak et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

“…A reduction of mature newborn neurons has been determined in male σ 1 R À / À mice (Sha et al, 2013). During pregnancy, the number of newborn neurons in the DG is significantly increased followed by a rapid decline after parturition (Pawluski and Galea, 2007;Furuta and Bridges, 2005).…”

Section: Introductionmentioning

confidence: 99%

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

Sha¹,

Hong²,

Qu³

et al. 2015

European Neuropsychopharmacology

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Effects of dextromethorphan on glial cell function: Proliferation, maturation, and protection from cytotoxic molecules

Lisak

Nedelkoska

Benjamins

2014

Glia

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Dextromethorphan (DM), a sigma receptor agonist and NMDA receptor antagonist, protects neurons from glutamate excitotoxicity, hypoxia and ischemia, and inhibits microglial activation, but its effects on differentiation and protection of cells in the oligodendroglial lineage are unknown. It is important to protect oligodendroglia (OL) to prevent demyelination and preserve axons, and to protect oligodendroglial progenitors (OPC) to optimize myelination during development and remyelination following damage. Enriched glial cultures from newborn rat brain were used 1-2 days or 6-8 days after shakeoff for OPC or mature OL. DM had large effects on glial proliferation in less mature cultures in contrast to small variable effects in mature cultures; 1 μM DM stimulated proliferation of OPC by 4-fold, microglia (MG) by 2.5-fold and astroglia (AS) by 2-fold. In agreement with increased OPC proliferation, treatment of OPC with DM for 3 days increased the % of OPC relative to OL, with a smaller difference by 5 days, suggesting that maturation of OPC to OL was "catching up" by 5 days. DM at 2 and 20 μM protected both OL and OPC from killing by glutamate as well as NMDA, AMPA, quinolinic acid, staurosporine, and reactive oxygen species (ROS). DM did not protect against kynurenic acid, and only modestly against NO. These agents and DM were not toxic to AS or MG at the concentrations used. Thus, DM stimulates proliferation of OPC, and protects both OL and OPC against excitotoxic and inflammatory insults.

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Sigma‐1 Receptor Knockout Impairs Neurogenesis in Dentate Gyrus of Adult Hippocampus Via Down‐Regulation of NMDA Receptors

Abstract: The σ1 R deficiency impairs neurogenesis in DG through down-regulation of NMDArs.

Cited by 58 publications

References 56 publications

Stimulation of Sigma-1 Receptor Ameliorates Depressive-like Behaviors in CaMKIV Null Mice

Stimulation of Sigma-1 Receptor Ameliorates Depressive-like Behaviors in CaMKIV Null Mice

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

Effects of dextromethorphan on glial cell function: Proliferation, maturation, and protection from cytotoxic molecules

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