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BDNF-TrkB signaling through Erk1/2 MAPK phosphorylation mediates the enhancement of fear memory induced by glucocorticoids.

Revest JM, Le Roux A, Roullot-Lacarrière V, Kaouane N, Vallée M, Kasanetz F, Rougé-Pont F, Tronche F, Desmedt A, Piazza PV - Mol. Psychiatry (2013)

Bottom Line: However, the molecular mechanism mediating this effect of GC remains unknown.We identified the tPA-BDNF-TrkB signaling pathway as the upstream molecular effectors of GR-mediated phosphorylation of Erk1/2(MAPK) responsible for the enhancement of contextual fear memory.These findings complete our knowledge of the molecular cascade through which GC enhance contextual fear memory and highlight the role of tPA-BDNF-TrkB-Erk1/2(MAPK) signaling pathways as one of the core effectors of stress-related effects of GC.

View Article: PubMed Central - PubMed

Affiliation: 1] INSERM U862, Neurocentre Magendie, Pathophysiology of Addiction, Bordeaux, France [2] Pathophysiology of Neuronal Plasticity, Université de Bordeaux, Bordeaux, France.

ABSTRACT
Activation of glucocorticoid receptors (GR) by glucocorticoid hormones (GC) enhances contextual fear memories through the activation of the Erk1/2(MAPK) signaling pathway. However, the molecular mechanism mediating this effect of GC remains unknown. Here we used complementary molecular and behavioral approaches in mice and rats and in genetically modified mice in which the GR was conditionally deleted (GR(NesCre)). We identified the tPA-BDNF-TrkB signaling pathway as the upstream molecular effectors of GR-mediated phosphorylation of Erk1/2(MAPK) responsible for the enhancement of contextual fear memory. These findings complete our knowledge of the molecular cascade through which GC enhance contextual fear memory and highlight the role of tPA-BDNF-TrkB-Erk1/2(MAPK) signaling pathways as one of the core effectors of stress-related effects of GC.

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Stress-induced activation of the glucocorticoid receptor (GR) in the hippocampus stimulates pro-brain-derived neurotrophic factor (pro-BDNF) expression and its processing to mature BDNF. Comparison of the expression of pro-BDNF and BDNF proteins in wild-type (WT) and GRNesCre mice, before (t0), 30 and 120 min after the onset of 30 min of restraint stress. Nuclear (for GR) and cytoplasmic hippocampal extracts were analyzed by western blot. X-Ray films were quantified by densitometry (OD). *P<0.05; **P<0.005, ***P<0.001 in comparison with t0 of each group. #P<0.05, ##P<0.005, ###P<0.001 in comparison with the corresponding time point of WT. Newman-Keuls post-hoc test after analysis of variance.
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fig1: Stress-induced activation of the glucocorticoid receptor (GR) in the hippocampus stimulates pro-brain-derived neurotrophic factor (pro-BDNF) expression and its processing to mature BDNF. Comparison of the expression of pro-BDNF and BDNF proteins in wild-type (WT) and GRNesCre mice, before (t0), 30 and 120 min after the onset of 30 min of restraint stress. Nuclear (for GR) and cytoplasmic hippocampal extracts were analyzed by western blot. X-Ray films were quantified by densitometry (OD). *P<0.05; **P<0.005, ***P<0.001 in comparison with t0 of each group. #P<0.05, ##P<0.005, ###P<0.001 in comparison with the corresponding time point of WT. Newman-Keuls post-hoc test after analysis of variance.

Mentions: In control littermate mice (WT), restraint stress induces translocation of the GR and increases the expression of pro-BDNF. This expression is maximal immediately after stress and is maintained 2 h later. BDNF levels increases 30 min after the beginning of the stress and returns to basal level after 2 h. In GRNesCre mice, BDNF levels were reduced in basal conditions but no significant changes were observed in both pro-BDNF expression and in BDNF levels after stress, although a trend to decrease in pro-BDNF and to increase in BDNF were observed (Figure 1). This non-significant trend to increase in BDNF in GRNesCre mice could correspond to a residual GR-independent proteolytic processing of the initial pool of pro-BDNF that consequently decreases in these mice, as its stress-induced increase is prevented by GR deletion.


BDNF-TrkB signaling through Erk1/2 MAPK phosphorylation mediates the enhancement of fear memory induced by glucocorticoids.

Revest JM, Le Roux A, Roullot-Lacarrière V, Kaouane N, Vallée M, Kasanetz F, Rougé-Pont F, Tronche F, Desmedt A, Piazza PV - Mol. Psychiatry (2013)

Stress-induced activation of the glucocorticoid receptor (GR) in the hippocampus stimulates pro-brain-derived neurotrophic factor (pro-BDNF) expression and its processing to mature BDNF. Comparison of the expression of pro-BDNF and BDNF proteins in wild-type (WT) and GRNesCre mice, before (t0), 30 and 120 min after the onset of 30 min of restraint stress. Nuclear (for GR) and cytoplasmic hippocampal extracts were analyzed by western blot. X-Ray films were quantified by densitometry (OD). *P<0.05; **P<0.005, ***P<0.001 in comparison with t0 of each group. #P<0.05, ##P<0.005, ###P<0.001 in comparison with the corresponding time point of WT. Newman-Keuls post-hoc test after analysis of variance.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4195976&req=5

fig1: Stress-induced activation of the glucocorticoid receptor (GR) in the hippocampus stimulates pro-brain-derived neurotrophic factor (pro-BDNF) expression and its processing to mature BDNF. Comparison of the expression of pro-BDNF and BDNF proteins in wild-type (WT) and GRNesCre mice, before (t0), 30 and 120 min after the onset of 30 min of restraint stress. Nuclear (for GR) and cytoplasmic hippocampal extracts were analyzed by western blot. X-Ray films were quantified by densitometry (OD). *P<0.05; **P<0.005, ***P<0.001 in comparison with t0 of each group. #P<0.05, ##P<0.005, ###P<0.001 in comparison with the corresponding time point of WT. Newman-Keuls post-hoc test after analysis of variance.
Mentions: In control littermate mice (WT), restraint stress induces translocation of the GR and increases the expression of pro-BDNF. This expression is maximal immediately after stress and is maintained 2 h later. BDNF levels increases 30 min after the beginning of the stress and returns to basal level after 2 h. In GRNesCre mice, BDNF levels were reduced in basal conditions but no significant changes were observed in both pro-BDNF expression and in BDNF levels after stress, although a trend to decrease in pro-BDNF and to increase in BDNF were observed (Figure 1). This non-significant trend to increase in BDNF in GRNesCre mice could correspond to a residual GR-independent proteolytic processing of the initial pool of pro-BDNF that consequently decreases in these mice, as its stress-induced increase is prevented by GR deletion.

Bottom Line: However, the molecular mechanism mediating this effect of GC remains unknown.We identified the tPA-BDNF-TrkB signaling pathway as the upstream molecular effectors of GR-mediated phosphorylation of Erk1/2(MAPK) responsible for the enhancement of contextual fear memory.These findings complete our knowledge of the molecular cascade through which GC enhance contextual fear memory and highlight the role of tPA-BDNF-TrkB-Erk1/2(MAPK) signaling pathways as one of the core effectors of stress-related effects of GC.

View Article: PubMed Central - PubMed

Affiliation: 1] INSERM U862, Neurocentre Magendie, Pathophysiology of Addiction, Bordeaux, France [2] Pathophysiology of Neuronal Plasticity, Université de Bordeaux, Bordeaux, France.

ABSTRACT
Activation of glucocorticoid receptors (GR) by glucocorticoid hormones (GC) enhances contextual fear memories through the activation of the Erk1/2(MAPK) signaling pathway. However, the molecular mechanism mediating this effect of GC remains unknown. Here we used complementary molecular and behavioral approaches in mice and rats and in genetically modified mice in which the GR was conditionally deleted (GR(NesCre)). We identified the tPA-BDNF-TrkB signaling pathway as the upstream molecular effectors of GR-mediated phosphorylation of Erk1/2(MAPK) responsible for the enhancement of contextual fear memory. These findings complete our knowledge of the molecular cascade through which GC enhance contextual fear memory and highlight the role of tPA-BDNF-TrkB-Erk1/2(MAPK) signaling pathways as one of the core effectors of stress-related effects of GC.

Show MeSH