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The enhancement of stress-related memory by glucocorticoids depends on synapsin-Ia/Ib.

Revest JM, Kaouane N, Mondin M, Le Roux A, Rougé-Pont F, Vallée M, Barik J, Tronche F, Desmedt A, Piazza PV - Mol. Psychiatry (2010)

Bottom Line: Stress and glucocorticoid-induced activation of the GR modulate synapsin-Ia/Ib through two complementary mechanisms.First, glucocorticoids driving Egr-1 expression increase the expression of synapsin-Ia/Ib, and second, glucocorticoids driving MAPK activation increase its phosphorylation.In conclusion, our data provide a complete molecular pathway (GR/Egr-1/MAPK/Syn-Ia/Ib) through which stress and glucocorticoids enhance the memory of stress-related events and highlight the function of synapsin-Ia/Ib as molecular effector of the behavioral effects of stress.

View Article: PubMed Central - PubMed

Affiliation: INSERM U862, Neurocentre Magendie, Pathophysiology of Addiction group, Bordeaux, France. jean-michel.revest@inserm.fr

ABSTRACT
The activation of glucocorticoid receptors (GR) by glucocorticoids increases stress-related memory through the activation of the MAPK signaling pathway and the downstream transcription factor Egr-1. Here, using converging in vitro and in vivo approaches, respectively, GR-expressing cell lines, culture of hippocampal neurons, and GR genetically modified mice (GR(NesCre)), we identified synapsin-Ia/Ib as one of the effectors of the glucocorticoid signaling cascade. Stress and glucocorticoid-induced activation of the GR modulate synapsin-Ia/Ib through two complementary mechanisms. First, glucocorticoids driving Egr-1 expression increase the expression of synapsin-Ia/Ib, and second, glucocorticoids driving MAPK activation increase its phosphorylation. Finally, we showed that blocking fucosylation of synapsin-Ia/Ib in the hippocampus inhibits its expression and prevents the glucocorticoid-mediated increase in stress-related memory. In conclusion, our data provide a complete molecular pathway (GR/Egr-1/MAPK/Syn-Ia/Ib) through which stress and glucocorticoids enhance the memory of stress-related events and highlight the function of synapsin-Ia/Ib as molecular effector of the behavioral effects of stress.

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Synapsin-Ia/Ib mediates the enhancement of contextual fear conditioning induced by glucocorticoids. (a) Percentage of conditioned freezing (mean±s.e.m.) displayed by mice re-exposed for 4 min to the conditioning context 24 h after conditioning with either high (0.7 mA footshock; n=12) or low shock intensity (0.3 mA footshock; n=11) and receiving a post-training intra-hippocampal infusion of either vehicle (n=11), 2-dGal (n=11; 400 m per side), corticosterone (n=12; 10 ng per side), or corticosterone+2-dGal (n=12). (b) Western blot analysis and quantification of synapsin-Ia/Ib hippocampal expression in the presence or absence of the inhibitor of fucosylation 2-dGal (400 m per side). βIII-tubulin was used as a loading control; 2 h post-hippocampal infusion of 2-dGal, proteins were extracted, analyzed by western blot, and quantified by densitometry (optical density OD, mean±s.e.m., n=4). **P<0.005, ***P<0.0001, in comparison with all the other groups, Newman–Keuls and Scheffe post hoc test after ANOVA.
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fig4: Synapsin-Ia/Ib mediates the enhancement of contextual fear conditioning induced by glucocorticoids. (a) Percentage of conditioned freezing (mean±s.e.m.) displayed by mice re-exposed for 4 min to the conditioning context 24 h after conditioning with either high (0.7 mA footshock; n=12) or low shock intensity (0.3 mA footshock; n=11) and receiving a post-training intra-hippocampal infusion of either vehicle (n=11), 2-dGal (n=11; 400 m per side), corticosterone (n=12; 10 ng per side), or corticosterone+2-dGal (n=12). (b) Western blot analysis and quantification of synapsin-Ia/Ib hippocampal expression in the presence or absence of the inhibitor of fucosylation 2-dGal (400 m per side). βIII-tubulin was used as a loading control; 2 h post-hippocampal infusion of 2-dGal, proteins were extracted, analyzed by western blot, and quantified by densitometry (optical density OD, mean±s.e.m., n=4). **P<0.005, ***P<0.0001, in comparison with all the other groups, Newman–Keuls and Scheffe post hoc test after ANOVA.

Mentions: We, therefore, examined the effects of an intra-hippocampal infusion of 2-dGal both on the expression of synapsin-I and on the enhancement of hippocampal-dependent contextual fear conditioning8, 28 induced by corticosterone (Figure 4). Intra-hippocampal infusion of corticosterone immediately after training increased the conditioned fear induced by an electric shock of low intensity (0.3 mA footshock) inducing a response similar to the one obtained with an electric shock of high intensity (0.7 mA footshock) (Figure 4a). However, the enhancing effect of corticosterone on contextual fear conditioning was completely abolished when 2-dGal (400 m per side) was infused concomitantly with corticosterone (Figure 4a). To verify the effect of corticosterone and 2-dGal infusion on synapsin-I, a group of animals was killed 2 h after the hippocampal infusions. Hippocampal proteins were then extracted and analyzed by western blot. We found that hippocampal infusion of corticosterone stimulates synapsin-Ia/Ib expression and that this increase was largely blocked by 2-dGal infusion (Figure 4b).


The enhancement of stress-related memory by glucocorticoids depends on synapsin-Ia/Ib.

Revest JM, Kaouane N, Mondin M, Le Roux A, Rougé-Pont F, Vallée M, Barik J, Tronche F, Desmedt A, Piazza PV - Mol. Psychiatry (2010)

Synapsin-Ia/Ib mediates the enhancement of contextual fear conditioning induced by glucocorticoids. (a) Percentage of conditioned freezing (mean±s.e.m.) displayed by mice re-exposed for 4 min to the conditioning context 24 h after conditioning with either high (0.7 mA footshock; n=12) or low shock intensity (0.3 mA footshock; n=11) and receiving a post-training intra-hippocampal infusion of either vehicle (n=11), 2-dGal (n=11; 400 m per side), corticosterone (n=12; 10 ng per side), or corticosterone+2-dGal (n=12). (b) Western blot analysis and quantification of synapsin-Ia/Ib hippocampal expression in the presence or absence of the inhibitor of fucosylation 2-dGal (400 m per side). βIII-tubulin was used as a loading control; 2 h post-hippocampal infusion of 2-dGal, proteins were extracted, analyzed by western blot, and quantified by densitometry (optical density OD, mean±s.e.m., n=4). **P<0.005, ***P<0.0001, in comparison with all the other groups, Newman–Keuls and Scheffe post hoc test after ANOVA.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC2990189&req=5

fig4: Synapsin-Ia/Ib mediates the enhancement of contextual fear conditioning induced by glucocorticoids. (a) Percentage of conditioned freezing (mean±s.e.m.) displayed by mice re-exposed for 4 min to the conditioning context 24 h after conditioning with either high (0.7 mA footshock; n=12) or low shock intensity (0.3 mA footshock; n=11) and receiving a post-training intra-hippocampal infusion of either vehicle (n=11), 2-dGal (n=11; 400 m per side), corticosterone (n=12; 10 ng per side), or corticosterone+2-dGal (n=12). (b) Western blot analysis and quantification of synapsin-Ia/Ib hippocampal expression in the presence or absence of the inhibitor of fucosylation 2-dGal (400 m per side). βIII-tubulin was used as a loading control; 2 h post-hippocampal infusion of 2-dGal, proteins were extracted, analyzed by western blot, and quantified by densitometry (optical density OD, mean±s.e.m., n=4). **P<0.005, ***P<0.0001, in comparison with all the other groups, Newman–Keuls and Scheffe post hoc test after ANOVA.
Mentions: We, therefore, examined the effects of an intra-hippocampal infusion of 2-dGal both on the expression of synapsin-I and on the enhancement of hippocampal-dependent contextual fear conditioning8, 28 induced by corticosterone (Figure 4). Intra-hippocampal infusion of corticosterone immediately after training increased the conditioned fear induced by an electric shock of low intensity (0.3 mA footshock) inducing a response similar to the one obtained with an electric shock of high intensity (0.7 mA footshock) (Figure 4a). However, the enhancing effect of corticosterone on contextual fear conditioning was completely abolished when 2-dGal (400 m per side) was infused concomitantly with corticosterone (Figure 4a). To verify the effect of corticosterone and 2-dGal infusion on synapsin-I, a group of animals was killed 2 h after the hippocampal infusions. Hippocampal proteins were then extracted and analyzed by western blot. We found that hippocampal infusion of corticosterone stimulates synapsin-Ia/Ib expression and that this increase was largely blocked by 2-dGal infusion (Figure 4b).

Bottom Line: Stress and glucocorticoid-induced activation of the GR modulate synapsin-Ia/Ib through two complementary mechanisms.First, glucocorticoids driving Egr-1 expression increase the expression of synapsin-Ia/Ib, and second, glucocorticoids driving MAPK activation increase its phosphorylation.In conclusion, our data provide a complete molecular pathway (GR/Egr-1/MAPK/Syn-Ia/Ib) through which stress and glucocorticoids enhance the memory of stress-related events and highlight the function of synapsin-Ia/Ib as molecular effector of the behavioral effects of stress.

View Article: PubMed Central - PubMed

Affiliation: INSERM U862, Neurocentre Magendie, Pathophysiology of Addiction group, Bordeaux, France. jean-michel.revest@inserm.fr

ABSTRACT
The activation of glucocorticoid receptors (GR) by glucocorticoids increases stress-related memory through the activation of the MAPK signaling pathway and the downstream transcription factor Egr-1. Here, using converging in vitro and in vivo approaches, respectively, GR-expressing cell lines, culture of hippocampal neurons, and GR genetically modified mice (GR(NesCre)), we identified synapsin-Ia/Ib as one of the effectors of the glucocorticoid signaling cascade. Stress and glucocorticoid-induced activation of the GR modulate synapsin-Ia/Ib through two complementary mechanisms. First, glucocorticoids driving Egr-1 expression increase the expression of synapsin-Ia/Ib, and second, glucocorticoids driving MAPK activation increase its phosphorylation. Finally, we showed that blocking fucosylation of synapsin-Ia/Ib in the hippocampus inhibits its expression and prevents the glucocorticoid-mediated increase in stress-related memory. In conclusion, our data provide a complete molecular pathway (GR/Egr-1/MAPK/Syn-Ia/Ib) through which stress and glucocorticoids enhance the memory of stress-related events and highlight the function of synapsin-Ia/Ib as molecular effector of the behavioral effects of stress.

Show MeSH
Related in: MedlinePlus