title: Stimulation of Sigma-1 Receptor Ameliorates Depressive-like Behaviors in CaMKIV Null Mice.
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.
authors.affiliation: Department 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.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Moriguchi
authors.affiliation: Department of Anatomy, Kitasato University School of Medicine, Sagamihara, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sakagami
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai, Miyagi, 980-8578, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yabuki
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai, Miyagi, 980-8578, Japan.
authors.forename: Yuzuru
authors.initials: Y
authors.lastname: Sasaki
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai, Miyagi, 980-8578, Japan.
authors.forename: Hisanao
authors.initials: H
authors.lastname: Izumi
authors.affiliation: Department of Pharmacy, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Pharmacy, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Han
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai, Miyagi, 980-8578, Japan. kfukunaga@m.tohoku.ac.jp.
authors.forename: Kohji
authors.initials: K
authors.lastname: Fukunaga
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis / Q000235:genetics; D056654:CA3 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism; D064026:Calbindins / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4 / Q000172:deficiency*; D018891:Dentate Gyrus / Q000187:drug effects / Q000378:metabolism; D003863:Depression / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D016666:Fluvoxamine / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D007103:Immobilization; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D055495:Neurogenesis / Q000187:drug effects; D017374:Paroxetine / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D017480:Receptors, sigma / Q000819:agonists* / Q000096:biosynthesis / Q000235:genetics; D000097605:Sigma-1 Receptor
chemical_list: D000255:Adenosine Triphosphate; D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D064026:Calbindins; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D016666:Fluvoxamine; D009419:Nerve Tissue Proteins; D017374:Paroxetine; D010879:Piperazines; D051057:Proto-Oncogene Proteins c-akt; D016194:Receptors, N-Methyl-D-Aspartate; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C101789:SA 4503; C514862:Akt1 protein, mouse; C517685:Camk4 protein, mouse
keywords: CaMKIV null mice; Depressive-like behaviors; Hippocampal neurogenesis; Sigma-1R