title: Stimulation of the sigma-1 receptor by DHEA enhances synaptic efficacy and neurogenesis in the hippocampal dentate gyrus of olfactory bulbectomized mice.
abstract: Dehydroepiandrosterone (DHEA) is the most abundant neurosteroid synthesized de novo in the central nervous system. We previously reported that stimulation of the sigma-1 receptor by DHEA improves cognitive function by activating calcium/calmodulin-dependent protein kinase II (CaMKII), protein kinase C and extracellular signal-regulated kinase in the hippocampus in olfactory bulbectomized (OBX) mice. Here, we asked whether DHEA enhances neurogenesis in the subgranular zone of the hippocampal dentate gyrus (DG) and improves depressive-like behaviors observed in OBX mice. Chronic treatment with DHEA at 30 or 60 mg/kg p.o. for 14 days significantly improved hippocampal LTP impaired in OBX mice concomitant with increased CaMKII autophosphorylation and GluR1 (Ser-831) phosphorylation in the DG. Chronic DHEA treatment also ameliorated depressive-like behaviors in OBX mice, as assessed by tail suspension and forced swim tests, while a single DHEA treatment had no affect. DHEA treatment also significantly increased the number of BrdU-positive neurons in the subgranular zone of the DG of OBX mice, an increase inhibited by treatment with NE-100, a sigma-1 receptor antagonist. DHEA treatment also significantly increased phosphorylation of Akt (Ser-473), Akt (Ser-308) and ERK in the DG. Furthermore, GSK-3β (Ser-9) phosphorylation increased in the DG of OBX mice possibly accounting for increased neurogenesis through Akt activation. Finally, we confirmed that DHEA treatment of OBX mice increases the number of BrdU-positive neurons co-expressing β-catenin, a downstream GSK-3βtarget. Overall, we conclude that sigma-1 receptor stimulation by DHEA ameliorates OBX-induced depressive-like behaviors by increasing neurogenesis in the DG through activation of the Akt/GSK-3β/β-catenin pathway.
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan. shigeki@m.tohoku.ac.jp
authors.forename: Shigeki
authors.initials: S
authors.lastname: Moriguchi
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Shinoda
authors.forename: Yui
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Yuzuru
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Kosuke
authors.initials: K
authors.lastname: Miyajima
authors.forename: Hideaki
authors.initials: H
authors.lastname: Tagashira
authors.forename: Kohji
authors.initials: K
authors.lastname: Fukunaga
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D003687:Dehydroepiandrosterone / Q000494:pharmacology* / Q000627:therapeutic use; D018891:Dentate Gyrus / Q000166:cytology* / Q000187:drug effects* / Q000502:physiology; D003863:Depression / Q000188:drug therapy; D004789:Enzyme Activation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D017774:Long-Term Potentiation / Q000187:drug effects; D051379:Mice; D055495:Neurogenesis / Q000187:drug effects*; D009830:Olfactory Bulb / Q000601:surgery*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017480:Receptors, sigma / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013569:Synapses / Q000187:drug effects* / Q000502:physiology; D051176:beta Catenin / Q000378:metabolism; D000097605:Sigma-1 Receptor
chemical_list: D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D003687:Dehydroepiandrosterone; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D017480:Receptors, sigma; D051176:beta Catenin; D000097605:Sigma-1 Receptor; C000605507:Gsk3b protein, mouse