Stimulation of the sigma-1 Receptor by DHEA Enhances Synaptic Efficacy and Neurogenesis in the Hippocampal Dentate Gyrus of Olfactory Bulbectomized Mice

PLoS One. 2013 Apr 8;8(4):e60863. doi: 10.1371/journal.pone.0060863. Print 2013.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
  • Dehydroepiandrosterone / pharmacology*
  • Dehydroepiandrosterone / therapeutic use
  • Dentate Gyrus / cytology*
  • Dentate Gyrus / drug effects*
  • Dentate Gyrus / physiology
  • Depression / drug therapy
  • Enzyme Activation / drug effects
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Long-Term Potentiation / drug effects
  • Mice
  • Neurogenesis / drug effects*
  • Olfactory Bulb / surgery*
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptors, sigma / metabolism*
  • Signal Transduction / drug effects
  • Synapses / drug effects*
  • Synapses / physiology
  • beta Catenin / metabolism

Substances

  • Receptors, sigma
  • beta Catenin
  • sigma-1 receptor
  • Dehydroepiandrosterone
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Proto-Oncogene Proteins c-akt
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Glycogen Synthase Kinase 3

Grant support

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.) and the Pharmacological Research Foundation, Tokyo (to S.M.), the Research Foundation for Pharmaceutical Sciences (to S.M.), the Smoking Research Foundation (to K.F.), the Takeda Science Foundation (to S.M.), the NISHINOMIYA Basic Research Fund (Japan) (to S.M.), the Suzuken Memorial Foundation (to S.M.), the HIROMI Medical Research Foundation (to S.M.). Funding was provided by the Tohoku University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.