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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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Enhancement of contextual fear memory induced by glucocorticoid (GC) requires pro-brain-derived neurotrophic factor (pro-BDNF) proteolytic processing by tPA/Plasmin system. Western blot showing purified (a) BDNF and (b) PAI-1 proteins injected into the hippocampus of C57/BL6J mice. (c) Percentage of freezing was measured for 2 min to the conditioning context 24 h after conditioning with either high (H, black bar) or low shock intensity (L, white bar) and receiving a post-training intra-hippocampal infusion of either corticosterone (dark gray bar), corticosterone+BDNF (light gray bar) with or without tPA inhibitor; PAI-1 (striped bars). Fisher's PLSD post-hoc test after analysis of variance. ***P<0.001 compared with high. $$$P<0.001 and $P<0.05 compared with high and low+Cort and low+Cort+PAI-1+BDNF (striped light gray bar), respectively. #P<0.05 compared with low+Cort and low+Cort+PAI-1+BDNF, respectively.
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fig4: Enhancement of contextual fear memory induced by glucocorticoid (GC) requires pro-brain-derived neurotrophic factor (pro-BDNF) proteolytic processing by tPA/Plasmin system. Western blot showing purified (a) BDNF and (b) PAI-1 proteins injected into the hippocampus of C57/BL6J mice. (c) Percentage of freezing was measured for 2 min to the conditioning context 24 h after conditioning with either high (H, black bar) or low shock intensity (L, white bar) and receiving a post-training intra-hippocampal infusion of either corticosterone (dark gray bar), corticosterone+BDNF (light gray bar) with or without tPA inhibitor; PAI-1 (striped bars). Fisher's PLSD post-hoc test after analysis of variance. ***P<0.001 compared with high. $$$P<0.001 and $P<0.05 compared with high and low+Cort and low+Cort+PAI-1+BDNF (striped light gray bar), respectively. #P<0.05 compared with low+Cort and low+Cort+PAI-1+BDNF, respectively.

Mentions: The results of the previous experiments indicated that GC- and stress-induced activation of GR increase tPA expression (Figure 2) and BDNF-TrkB molecular signaling, which in turn induce Erk1/2MAPK phoshorylation to finally enhance contextual fear memory (Figures 1 and 3). However, these results do not demonstrate that the enhancing effects of GC on contextual fear memory occurring through the activation of the BDNF-TrkB-Erk1/2MAPK signaling cascade require the activity of tPA to cleave pro-BDNF in BDNF. To test this hypothesis, we analyzed if the inhibition of the activity of tPA would block the enhancement of contextual fear memory mediated by the GC-activated GR-BDNF-TrkB-Erk1/2MAPK signaling cascade. For this purpose, we used the tPA inhibitor PAI-1 (plasminogen activator inhibitor-1)32 to prevent pro-BDNF proteolytic processing into mature BDNF. The infusion of PAI-1 in the hippocampus, immediately after conditioning, blocked the increase in fear conditioning induced by a shock of high intensity (H+PAI-1, Figures 4b and c) or by the infusion of corticosterone after a shock of low intensity (L+Cort+PAI-1, Figures 4b and c). The effects of PAI-1 were mediated by the inhibition of the production of mature BDNF, as PAI-1-induced inhibition of fear memory was rescued by the concomitant infusion of mature BDNF (L+Cort+PAI-1+BDNF, Figures 4a–c).


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)

Enhancement of contextual fear memory induced by glucocorticoid (GC) requires pro-brain-derived neurotrophic factor (pro-BDNF) proteolytic processing by tPA/Plasmin system. Western blot showing purified (a) BDNF and (b) PAI-1 proteins injected into the hippocampus of C57/BL6J mice. (c) Percentage of freezing was measured for 2 min to the conditioning context 24 h after conditioning with either high (H, black bar) or low shock intensity (L, white bar) and receiving a post-training intra-hippocampal infusion of either corticosterone (dark gray bar), corticosterone+BDNF (light gray bar) with or without tPA inhibitor; PAI-1 (striped bars). Fisher's PLSD post-hoc test after analysis of variance. ***P<0.001 compared with high. $$$P<0.001 and $P<0.05 compared with high and low+Cort and low+Cort+PAI-1+BDNF (striped light gray bar), respectively. #P<0.05 compared with low+Cort and low+Cort+PAI-1+BDNF, respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig4: Enhancement of contextual fear memory induced by glucocorticoid (GC) requires pro-brain-derived neurotrophic factor (pro-BDNF) proteolytic processing by tPA/Plasmin system. Western blot showing purified (a) BDNF and (b) PAI-1 proteins injected into the hippocampus of C57/BL6J mice. (c) Percentage of freezing was measured for 2 min to the conditioning context 24 h after conditioning with either high (H, black bar) or low shock intensity (L, white bar) and receiving a post-training intra-hippocampal infusion of either corticosterone (dark gray bar), corticosterone+BDNF (light gray bar) with or without tPA inhibitor; PAI-1 (striped bars). Fisher's PLSD post-hoc test after analysis of variance. ***P<0.001 compared with high. $$$P<0.001 and $P<0.05 compared with high and low+Cort and low+Cort+PAI-1+BDNF (striped light gray bar), respectively. #P<0.05 compared with low+Cort and low+Cort+PAI-1+BDNF, respectively.
Mentions: The results of the previous experiments indicated that GC- and stress-induced activation of GR increase tPA expression (Figure 2) and BDNF-TrkB molecular signaling, which in turn induce Erk1/2MAPK phoshorylation to finally enhance contextual fear memory (Figures 1 and 3). However, these results do not demonstrate that the enhancing effects of GC on contextual fear memory occurring through the activation of the BDNF-TrkB-Erk1/2MAPK signaling cascade require the activity of tPA to cleave pro-BDNF in BDNF. To test this hypothesis, we analyzed if the inhibition of the activity of tPA would block the enhancement of contextual fear memory mediated by the GC-activated GR-BDNF-TrkB-Erk1/2MAPK signaling cascade. For this purpose, we used the tPA inhibitor PAI-1 (plasminogen activator inhibitor-1)32 to prevent pro-BDNF proteolytic processing into mature BDNF. The infusion of PAI-1 in the hippocampus, immediately after conditioning, blocked the increase in fear conditioning induced by a shock of high intensity (H+PAI-1, Figures 4b and c) or by the infusion of corticosterone after a shock of low intensity (L+Cort+PAI-1, Figures 4b and c). The effects of PAI-1 were mediated by the inhibition of the production of mature BDNF, as PAI-1-induced inhibition of fear memory was rescued by the concomitant infusion of mature BDNF (L+Cort+PAI-1+BDNF, Figures 4a–c).

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