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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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In vivo tPA expression in C57/Bl6J mice after stress (a), in GRNesCre mice compared with control littermates in basal condition (b) and in response to restraint stress (c), and in C57/Bl6J mice after corticosterone injection (d). (a) Stress-induced glucocorticoid receptor (GR) activates tPA in the hippocampus. Plasma corticosterone concentrations, western blot and densitometric analyses of GR, tPA and βIII-tubulin proteins from cytoplasmic and nuclear hippocampal extracts of C57/Bl6J mice were measured before (t0) and 30, 60 and 120 min after the onset of 30-min restraint stress. (b) Western blot and densitometric analyses of GR, tPA and βIII-tubulin proteins from cytoplasmic and nuclear hippocampal extracts carried out in basal condition in wild-type (WT) and GRNesCre mice. (c) Western blot and densitometric analyses of tPA and βIII-tubulin proteins from total hippocampal extracts of WT and GRNesCre mice, before (t0), 30 and 120 min after the onset of 30 min of restraint stress. (d) Western blot and densitometric analyses of tPA and βIII-tubulin proteins from total hippocampal extracts collected 1 h post intra-hippocampal infusion of corticosterone (10 ng per side) in C57/Bl6J mice. Cort, corticosterone, Csf, cerebrospinal fluid. *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. $P<0.05, $$P<0.005, $$$P<0.001 in comparison with the matched control (WT or Csf groups). Student's t-test.
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fig2: In vivo tPA expression in C57/Bl6J mice after stress (a), in GRNesCre mice compared with control littermates in basal condition (b) and in response to restraint stress (c), and in C57/Bl6J mice after corticosterone injection (d). (a) Stress-induced glucocorticoid receptor (GR) activates tPA in the hippocampus. Plasma corticosterone concentrations, western blot and densitometric analyses of GR, tPA and βIII-tubulin proteins from cytoplasmic and nuclear hippocampal extracts of C57/Bl6J mice were measured before (t0) and 30, 60 and 120 min after the onset of 30-min restraint stress. (b) Western blot and densitometric analyses of GR, tPA and βIII-tubulin proteins from cytoplasmic and nuclear hippocampal extracts carried out in basal condition in wild-type (WT) and GRNesCre mice. (c) Western blot and densitometric analyses of tPA and βIII-tubulin proteins from total hippocampal extracts of WT and GRNesCre mice, before (t0), 30 and 120 min after the onset of 30 min of restraint stress. (d) Western blot and densitometric analyses of tPA and βIII-tubulin proteins from total hippocampal extracts collected 1 h post intra-hippocampal infusion of corticosterone (10 ng per side) in C57/Bl6J mice. Cort, corticosterone, Csf, cerebrospinal fluid. *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. $P<0.05, $$P<0.005, $$$P<0.001 in comparison with the matched control (WT or Csf groups). Student's t-test.

Mentions: We first studied the effects of a restraint stress on the expression of tPA (Figure 2a). In C57/BL6J mice, 30 min of restraint stress increased plasma concentrations of corticosterone and transiently activated the GR, as indicated by the increase in the nuclear fraction of the GR 30 min after stress onset. Restraint stress also increased the expression of tPA that was maximal 30 min after stress, and still significantly elevated after 1 h (Figure 2a). We then analyzed tPA expression in GRNesCre mutant mice lacking the GR. In basal conditions, tPA expression was significantly reduced in GRNesCre mutant mice (Figure 2b). In addition, the increase in tPA observed in wild-type mice during stress was completely suppressed in GRNesCre mutant mice (Figure 2c).


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)

In vivo tPA expression in C57/Bl6J mice after stress (a), in GRNesCre mice compared with control littermates in basal condition (b) and in response to restraint stress (c), and in C57/Bl6J mice after corticosterone injection (d). (a) Stress-induced glucocorticoid receptor (GR) activates tPA in the hippocampus. Plasma corticosterone concentrations, western blot and densitometric analyses of GR, tPA and βIII-tubulin proteins from cytoplasmic and nuclear hippocampal extracts of C57/Bl6J mice were measured before (t0) and 30, 60 and 120 min after the onset of 30-min restraint stress. (b) Western blot and densitometric analyses of GR, tPA and βIII-tubulin proteins from cytoplasmic and nuclear hippocampal extracts carried out in basal condition in wild-type (WT) and GRNesCre mice. (c) Western blot and densitometric analyses of tPA and βIII-tubulin proteins from total hippocampal extracts of WT and GRNesCre mice, before (t0), 30 and 120 min after the onset of 30 min of restraint stress. (d) Western blot and densitometric analyses of tPA and βIII-tubulin proteins from total hippocampal extracts collected 1 h post intra-hippocampal infusion of corticosterone (10 ng per side) in C57/Bl6J mice. Cort, corticosterone, Csf, cerebrospinal fluid. *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. $P<0.05, $$P<0.005, $$$P<0.001 in comparison with the matched control (WT or Csf groups). Student's t-test.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig2: In vivo tPA expression in C57/Bl6J mice after stress (a), in GRNesCre mice compared with control littermates in basal condition (b) and in response to restraint stress (c), and in C57/Bl6J mice after corticosterone injection (d). (a) Stress-induced glucocorticoid receptor (GR) activates tPA in the hippocampus. Plasma corticosterone concentrations, western blot and densitometric analyses of GR, tPA and βIII-tubulin proteins from cytoplasmic and nuclear hippocampal extracts of C57/Bl6J mice were measured before (t0) and 30, 60 and 120 min after the onset of 30-min restraint stress. (b) Western blot and densitometric analyses of GR, tPA and βIII-tubulin proteins from cytoplasmic and nuclear hippocampal extracts carried out in basal condition in wild-type (WT) and GRNesCre mice. (c) Western blot and densitometric analyses of tPA and βIII-tubulin proteins from total hippocampal extracts of WT and GRNesCre mice, before (t0), 30 and 120 min after the onset of 30 min of restraint stress. (d) Western blot and densitometric analyses of tPA and βIII-tubulin proteins from total hippocampal extracts collected 1 h post intra-hippocampal infusion of corticosterone (10 ng per side) in C57/Bl6J mice. Cort, corticosterone, Csf, cerebrospinal fluid. *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. $P<0.05, $$P<0.005, $$$P<0.001 in comparison with the matched control (WT or Csf groups). Student's t-test.
Mentions: We first studied the effects of a restraint stress on the expression of tPA (Figure 2a). In C57/BL6J mice, 30 min of restraint stress increased plasma concentrations of corticosterone and transiently activated the GR, as indicated by the increase in the nuclear fraction of the GR 30 min after stress onset. Restraint stress also increased the expression of tPA that was maximal 30 min after stress, and still significantly elevated after 1 h (Figure 2a). We then analyzed tPA expression in GRNesCre mutant mice lacking the GR. In basal conditions, tPA expression was significantly reduced in GRNesCre mutant mice (Figure 2b). In addition, the increase in tPA observed in wild-type mice during stress was completely suppressed in GRNesCre mutant mice (Figure 2c).

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
Related in: MedlinePlus