Stimulation of Sigma-1 Receptor Ameliorates Depressive-like Behaviors in CaMKIV Null Mice
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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.
KeywordsSigma-1R CaMKIV null mice Depressive-like behaviors Hippocampal neurogenesis
Protein kinase B
Brain-derived neurotrophic factor
Calcium/calmodulin-dependent protein kinase II
Calcium/calmodulin-dependent protein kinase IV
cAMP-responsive element binding protein
Extracellular signal-regulated kinase
Field excitatory postsynaptic potentials
Selective serotonin reuptake inhibitors
This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science and Technology, and the Ministry of Health and Welfare of Japan (22390109 to K.F.; 20790398 to S.M.), the Smoking Research Foundation (to K.F.), the Takeda Science Foundation (to S.M.), the Suzuken Memorial Foundation (to S.M.), the Yokoyama Foundation for Clinical Pharmacology (to S.M.) and the Comprehensive Brain Science Network (CBSN).
S.M., H.S., Y.S., N.I., and Y.Y. performed the experiments. H.S. provided knockout mice. C.Z. and F.H. provided materials. S.M. and K.F. wrote the manuscript and designed the study.
Conflicts of Interest
The authors declare no competing financial interests.
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