Molecular Neurobiology

, Volume 52, Issue 3, pp 1210–1222 | Cite as

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

  • Shigeki MoriguchiEmail author
  • Hiroyuki Sakagami
  • Yasushi Yabuki
  • Yuzuru Sasaki
  • Hisanao Izumi
  • Chen Zhang
  • Feng Han
  • Kohji FukunagaEmail author


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.


Sigma-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


Dentate gyrus




Extracellular signal-regulated kinase


Endoplasmic/sacroplasmic reticulum


Field excitatory postsynaptic potentials


High-frequency stimulation


Long-term potentiation


N-methyl-d-aspartate receptor


Sigma-1 receptor


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).

Authors Contributions

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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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Shigeki Moriguchi
    • 1
    Email author
  • Hiroyuki Sakagami
    • 2
  • Yasushi Yabuki
    • 1
  • Yuzuru Sasaki
    • 1
  • Hisanao Izumi
    • 1
  • Chen Zhang
    • 3
  • Feng Han
    • 3
  • Kohji Fukunaga
    • 1
    Email author
  1. 1.Department of Pharmacology, Graduate School of Pharmaceutical SciencesTohoku UniversitySendaiJapan
  2. 2.Department of AnatomyKitasato University School of MedicineSagamiharaJapan
  3. 3.Department of Pharmacy, College of Pharmaceutical SciencesZhejiang UniversityHangzhouChina

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