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Stimulation of Sigma-1 Receptor Ameliorates Depressive-like Behaviors in CaMKIV Null Mice
Shigeki Moriguchi1, Hiroyuki Sakagami2, Yasushi Yabuki3
1Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai, Miyagi, 980-8578, Japan. shigeki@m.tohoku.ac.jp.
Abstract:
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.
Insights
Stimulating the Sigma-1 receptor (Sig-1R) with SA4503 or fluvoxamine improved depressive behaviors in mice lacking CaMKIV. This treatment enhanced hippocampal neurogenesis and brain-derived neurotrophic factor (BDNF) levels.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Sigma-1 receptor (Sig-1R) acts as a molecular chaperone, regulating calcium signaling between the endoplasmic reticulum and mitochondria.
- Calcium/calmodulin-dependent protein kinase IV (CaMKIV) null mice display depressive-like behaviors and impaired neurogenesis in the hippocampal dentate gyrus (DG).
Purpose of the Study:
- To investigate the therapeutic potential of Sig-1R stimulation in ameliorating depressive-like behaviors and associated neurobiological deficits in CaMKIV null mice.
- To explore the effects of Sig-1R agonists on hippocampal neurogenesis, BDNF expression, ATP production, and long-term potentiation (LTP).
Main Methods:
- Chronic administration of Sig-1R agonist SA4503 or selective serotonin reuptake inhibitor (SSRI) fluvoxamine to CaMKIV null mice for 14 days.
- Assessment of depressive-like behaviors, hippocampal neurogenesis (using BrdU incorporation), BDNF mRNA and protein levels, Akt phosphorylation, ATP production, and LTP.
- Comparison with paroxetine, an SSRI lacking Sig-1R affinity.
Main Results:
- Chronic Sig-1R stimulation significantly improved depressive-like behaviors in CaMKIV null mice, an effect not observed with paroxetine.
- Treatment rescued reduced numbers of BrdU-positive cells, decreased BDNF mRNA expression, and impaired Akt phosphorylation in the DG.
- Sig-1R stimulation normalized reduced ATP production and improved hippocampal LTP induction and maintenance, associated with increased CaMKII and GluA1 phosphorylation.
Conclusions:
- Chronic stimulation of the Sigma-1 receptor effectively ameliorates depressive-like behaviors in CaMKIV null mice.
- Sig-1R activation promotes hippocampal neurogenesis and enhances synaptic plasticity, offering a potential therapeutic strategy for depression.
