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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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Schematic model of GEMS molecular cascade mediating the enhancement of stress-related memories. During stress, the increase in glucocorticoid secretion (1) activates the glucocorticoid receptors (GR) inducing its nuclear translocation (2). GR trigger the synthesis of the transcription factor Egr-1 (3) and then the activation of the MAPK pathway (4), which further increases Egr-1 production (5). Egr-1 stimulates the transcription of synapsin-Ia/Ib (6), which increases the number of SVs bound to actin and in this way the pool of readily releasable neurotransmitters. Activated MAPK do not modify synapsin-I expression, but induce their phosphorylation (7). Phosphorylated synapsin-Ia/Ib releases SVs bound to actin (8) allowing their transport to the pre-synaptic membrane (9) and neurotransmitter release (10). The double action of GR-induced Egr-1 expression and MAPK activation on both synapsin-I synthesis and phosphorylation can guarantee a sustained increase in neurotransmitter release. Specifically, an increase in glutamate release is likely to mediate the enhancement of stress-related memories that can be blocked both by inhibiting MAPK phosphorylation and synapsin-I expression. This model is based on several studies, including ours, which are discussed in the main text.
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fig5: Schematic model of GEMS molecular cascade mediating the enhancement of stress-related memories. During stress, the increase in glucocorticoid secretion (1) activates the glucocorticoid receptors (GR) inducing its nuclear translocation (2). GR trigger the synthesis of the transcription factor Egr-1 (3) and then the activation of the MAPK pathway (4), which further increases Egr-1 production (5). Egr-1 stimulates the transcription of synapsin-Ia/Ib (6), which increases the number of SVs bound to actin and in this way the pool of readily releasable neurotransmitters. Activated MAPK do not modify synapsin-I expression, but induce their phosphorylation (7). Phosphorylated synapsin-Ia/Ib releases SVs bound to actin (8) allowing their transport to the pre-synaptic membrane (9) and neurotransmitter release (10). The double action of GR-induced Egr-1 expression and MAPK activation on both synapsin-I synthesis and phosphorylation can guarantee a sustained increase in neurotransmitter release. Specifically, an increase in glutamate release is likely to mediate the enhancement of stress-related memories that can be blocked both by inhibiting MAPK phosphorylation and synapsin-I expression. This model is based on several studies, including ours, which are discussed in the main text.

Mentions: With the results of the present experiment extending those published in an earlier paper, we can single out a complete molecular cascade that is involved in the mediation of stress-related memory (Figure 5). We have earlier shown that stress-induced glucocorticoids increase stress-related memories by activating the GR, which trigger a cascade of events starting with an increase in the expression of the transcription factor Egr-1 and followed by the activation of the MAPK pathway.8 We show here that the activation of Egr-1 by glucocorticoids increases the level of synapsin-I and that the activation of the MAPK pathway induces the phosphorylation of this protein. Silencing Egr-1 expression thus represses the increase in synapsin-Ia/Ib expression induced by glucocorticoids both in PC12 cells and in primary culture of hippocampal neurons. This effect is probably a direct one, as Egr-1 binds to responsive elements in the promoter region of the syn1 gene and is able to activate its transcription in vitro.35, 36, 37 In parallel, mitogen-activated protein kinase (Erk1/2) induces the phosphorylation of synapsin-I, but does not modify its expression. Thus, UO126-mediated blockade of MAPK phosphorylation largely reduced glucocorticoid-induced synapsin-I phosphorylation, but did not change the expression of synapsin-I.


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)

Schematic model of GEMS molecular cascade mediating the enhancement of stress-related memories. During stress, the increase in glucocorticoid secretion (1) activates the glucocorticoid receptors (GR) inducing its nuclear translocation (2). GR trigger the synthesis of the transcription factor Egr-1 (3) and then the activation of the MAPK pathway (4), which further increases Egr-1 production (5). Egr-1 stimulates the transcription of synapsin-Ia/Ib (6), which increases the number of SVs bound to actin and in this way the pool of readily releasable neurotransmitters. Activated MAPK do not modify synapsin-I expression, but induce their phosphorylation (7). Phosphorylated synapsin-Ia/Ib releases SVs bound to actin (8) allowing their transport to the pre-synaptic membrane (9) and neurotransmitter release (10). The double action of GR-induced Egr-1 expression and MAPK activation on both synapsin-I synthesis and phosphorylation can guarantee a sustained increase in neurotransmitter release. Specifically, an increase in glutamate release is likely to mediate the enhancement of stress-related memories that can be blocked both by inhibiting MAPK phosphorylation and synapsin-I expression. This model is based on several studies, including ours, which are discussed in the main text.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig5: Schematic model of GEMS molecular cascade mediating the enhancement of stress-related memories. During stress, the increase in glucocorticoid secretion (1) activates the glucocorticoid receptors (GR) inducing its nuclear translocation (2). GR trigger the synthesis of the transcription factor Egr-1 (3) and then the activation of the MAPK pathway (4), which further increases Egr-1 production (5). Egr-1 stimulates the transcription of synapsin-Ia/Ib (6), which increases the number of SVs bound to actin and in this way the pool of readily releasable neurotransmitters. Activated MAPK do not modify synapsin-I expression, but induce their phosphorylation (7). Phosphorylated synapsin-Ia/Ib releases SVs bound to actin (8) allowing their transport to the pre-synaptic membrane (9) and neurotransmitter release (10). The double action of GR-induced Egr-1 expression and MAPK activation on both synapsin-I synthesis and phosphorylation can guarantee a sustained increase in neurotransmitter release. Specifically, an increase in glutamate release is likely to mediate the enhancement of stress-related memories that can be blocked both by inhibiting MAPK phosphorylation and synapsin-I expression. This model is based on several studies, including ours, which are discussed in the main text.
Mentions: With the results of the present experiment extending those published in an earlier paper, we can single out a complete molecular cascade that is involved in the mediation of stress-related memory (Figure 5). We have earlier shown that stress-induced glucocorticoids increase stress-related memories by activating the GR, which trigger a cascade of events starting with an increase in the expression of the transcription factor Egr-1 and followed by the activation of the MAPK pathway.8 We show here that the activation of Egr-1 by glucocorticoids increases the level of synapsin-I and that the activation of the MAPK pathway induces the phosphorylation of this protein. Silencing Egr-1 expression thus represses the increase in synapsin-Ia/Ib expression induced by glucocorticoids both in PC12 cells and in primary culture of hippocampal neurons. This effect is probably a direct one, as Egr-1 binds to responsive elements in the promoter region of the syn1 gene and is able to activate its transcription in vitro.35, 36, 37 In parallel, mitogen-activated protein kinase (Erk1/2) induces the phosphorylation of synapsin-I, but does not modify its expression. Thus, UO126-mediated blockade of MAPK phosphorylation largely reduced glucocorticoid-induced synapsin-I phosphorylation, but did not change the expression of synapsin-I.

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