Stimulation of the sigma-1 receptor by DHEA enhances synaptic efficacy and neurogenesis in the hippocampal dentate gyrus of olfactory bulbectomized mice - PubMed (original) (raw)

Stimulation of the sigma-1 receptor by DHEA enhances synaptic efficacy and neurogenesis in the hippocampal dentate gyrus of olfactory bulbectomized mice

Shigeki Moriguchi et al. PLoS One. 2013.

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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.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1

Figure 1. DHEA ameliorates perturbed LTP in the DG of OBX mice.

A: Representative fEPSPs were recorded from the DG in sham-operated mice, OBX mice, DHEA (60 mg/kg p.o.)-treated OBX mice, and DHEA plus NE-100 (1 mg/kg p.o.)-treated OBX mice. B: Changes in fEPSP slope following HFS recorded in the DG were attenuated in OBX compared with sham-operated mice. DHEA treatment significantly improved LTP in OBX mice. NE-100 significantly inhibited enhancement of LTP mediated by DHEA in OBX mice. C: Changes in fEPSP slope following HFS are shown in sham-operated, OBX, DHEA-treated OBX, and DHEA plus NE-100-treated OBX mice at 1 or 60 min. Vertical lines show SEM. **, p<0.01 versus sham-operated mice. ++, p<0.01 versus OBX mice. ##, p<0.01 versus DHEA-treated OBX mice.

Figure 2

Figure 2. DHEA rescues reduced autophosphorylation of CaMKIIα (Thr-286) and phosphorylation of GluR1 (Ser-831) but does not alter phosphorylation of CaMKIV (Thr-196) or synapsin I (Ser-603) in the DG of OBX mice.

A: Representative images of immunoblots using antibodies against autophosphorylated CaMKII, CaMKII, phosphorylated CaMKIV (Thr-196), phosphorylated synapsin I (Ser-606), synapsin I, phosphorylated GluR1 (Ser-831) and GluR1. B: Quantitative analyses of autophosphorylated CaMKIIα (Thr-286) and phosphorylated CaMKIV (Thr-196), synapsin I (Ser-606) and GluR1 (Ser-831). Vertical lines show SEM. **, p<0.01 versus sham-operated mice. ++, p<0.01 versus OBX mice. ##, p<0.01 versus DHEA-treated OBX mice.

Figure 3

Figure 3. DHEA antagonizes depressive-like behaviors in OBX mice.

A: Immobility time in a tail suspension test was measured following a single administration of DHEA at 30 or 60 mg/kg p.o. 14 days after OBX surgery. No difference in immobility time was observed among OBX, or DHEA-treated OBX mice (Mann-Whitney U-test, n = 5 per group). B: Immobility time in the tail suspension test was measured after repeated, chronic administration of DHEA at 30 or 60 mg/kg p.o. for 12–13 days, starting 14 days after OBX surgery. DHEA rescued immobility time in OBX mice. NE-100 (1 mg/kg p.o.) pre-administration significantly inhibited decreased immobility time seen following DHEA treatment of OBX mice (Mann-Whitney U-test, n = 5 per group). C: Immobility time in a forced swim test was measured following a single administration of DHEA at 30 or 60 mg/kg p.o. 14 days after OBX surgery. No difference in immobility time was observed between OBX, or DHEA-treated OBX (Mann-Whitney U-test, n = 5 per group). D: Immobility time in a forced swim test was measured after repeated DHEA administration at 30 or 60 mg/kg p.o. for 12–13 days, starting 14 days after OBX operation. DHEA rescued immobility time seen in OBX mice. Pre-administration of NE-100 (1 mg/kg p.o.) significantly inhibited DHEA-mediated rescue of immobility time in OBX mice (Mann-Whitney U-test, n = 5 per group). Vertical lines show SEM. *, p<0.05; **, p<0.01 versus sham-operated mice. +, p<0.05; ++, p<0.01 versus OBX mice. #, p<0.05 versus DHEA-treated OBX mice.

Figure 4

Figure 4. DHEA treatment enhances hippocampal neurogenesis in OBX mice.

A: Confocal microscopy images showing double staining for BrdU (green), NeuN (red) and merged images in hippocampal slices 30 days after OBX surgery (n = 8). B: Quantitative analyses of the number of BrdU/NeuN double-positive cells in the DG (n = 8). Vertical lines show SEM. **, p<0.01 versus sham-operated mice. ++, p<0.01 versus OBX mice. ##, p<0.01 versus DHEA-treated OBX mice.

Figure 5

Figure 5. DHEA treatment restores reduced phosphorylation of Akt (Ser-473), Akt (Thr-308) and ERK in the DG of OBX mice.

A: Representative images of immunoblots using antibodies against phosphorylated Akt (Ser-473), phosphorylated Akt (Thr-308) and phosphorylated ERK. B: Quantitative analyses of phosphorylated Akt (Ser-473), phosphorylated Akt (Thr-308) and phosphorylated ERK. Vertical lines show SEM. **, p<0.01 versus sham-operated mice. +, p<0.05; ++, p<0.01versus OBX mice. ##, p<0.01 versus DHEA-treated OBX mice.

Figure 6

Figure 6. DHEA treatment antagonizes increased GSK-3β (Ser-9) phosphorylation seen in the DG of OBX mice and increases the number of BrdU-positive neurons showing nuclear β-catenin.

A: Representative images of immunoblots using antibodies against phosphorylated GSK-3β (Ser-9), phosphorylated mTOR (Ser-2448), phosphorylated CREB (Ser-133) and quantitative analyses of phosphorylated GSK-3β (Ser-9), phosphorylated mTOR (Ser-2448), and phosphorylated CREB (Ser-133). B: Confocal microscopy images showing double staining for BrdU (green), β-catenin (red) and merged images taken from hippocampal slices 30 days after OBX surgery. C: Quantitative analyses of the number of BrdU/β-catenin double-positive cells in the DG. Vertical lines show SEM. **, p<0.01 versus sham-operated mice. ++, p<0.01 versus OBX mice. ##, p<0.01 versus DHEA-treated OBX mice.

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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.

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