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Seizure-Induced Regulations of Amyloid-β, STEP61, and STEP61 Substrates Involved in Hippocampal Synaptic Plasticity.

Jang SS, Royston SE, Lee G, Wang S, Chung HJ - Neural Plast. (2016)

Bottom Line: Pathologic accumulation of soluble amyloid-β (Aβ) oligomers impairs synaptic plasticity and causes epileptic seizures, both of which contribute to cognitive dysfunction in AD.Here we show that a single episode of electroconvulsive seizures (ECS) increased protein expression of membrane-associated STriatal-Enriched protein tyrosine Phosphatase (STEP61) and decreased tyrosine-phosphorylation of its substrates N-methyl D-aspartate receptor (NMDAR) subunit GluN2B and extracellular signal regulated kinase 1/2 (ERK1/2) in the rat hippocampus at 2 days following a single ECS.Interestingly, a significant decrease in ERK1/2 expression and an increase in APP and Aβ levels were observed at 3-4 days following a single ECS when STEP61 level returned to the baseline.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Neuroscience Program, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.

ABSTRACT
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline. Pathologic accumulation of soluble amyloid-β (Aβ) oligomers impairs synaptic plasticity and causes epileptic seizures, both of which contribute to cognitive dysfunction in AD. However, whether seizures could regulate Aβ-induced synaptic weakening remains unclear. Here we show that a single episode of electroconvulsive seizures (ECS) increased protein expression of membrane-associated STriatal-Enriched protein tyrosine Phosphatase (STEP61) and decreased tyrosine-phosphorylation of its substrates N-methyl D-aspartate receptor (NMDAR) subunit GluN2B and extracellular signal regulated kinase 1/2 (ERK1/2) in the rat hippocampus at 2 days following a single ECS. Interestingly, a significant decrease in ERK1/2 expression and an increase in APP and Aβ levels were observed at 3-4 days following a single ECS when STEP61 level returned to the baseline. Given that pathologic levels of Aβ increase STEP61 activity and STEP61-mediated dephosphorylation of GluN2B and ERK1/2 leads to NMDAR internalization and ERK1/2 inactivation, we propose that upregulation of STEP61 and downregulation of GluN2B and ERK1/2 phosphorylation mediate compensatory weakening of synaptic strength in response to acute enhancement of hippocampal network activity, whereas delayed decrease in ERK1/2 expression and increase in APP and Aβ expression may contribute to the maintenance of this synaptic weakening.

No MeSH data available.


Related in: MedlinePlus

A single ECS and chronic ECS differently alter Tyr204/187-phosphorylation of ERK1/2 in the hippocampus. Immunoblot analysis for the phosphorylation of ERK1/2 at Tyr204/187 (Y204/187) and total ERK1/2 expression in the hippocampal crude membrane (P2) fraction following a single ECS (n = 5 rats per time point) (a) and chronic ECS (n = 6 rats per time point) (b). The ratio of the Tyr204/187-phosphorylated ERK1/2 band intensity over the β-actin band intensity (top graphs) and the ratio of total ERK1/2 band intensity over the β-actin band intensity (bottom graphs) were calculated per each time point and normalized to that of “no seizure” (NS) sham group. Data shown represent the mean band intensity ± SEM. (a) A single ECS transiently decreases the level of Tyr204/187-phosphorylated ERK1/2 in the hippocampus at 48 h (###p < 0.005, t-test) and total ERK1/2 expression at 72–96 h (∗p < 0.05) following a single ECS. (b) Chronic ECS significantly increases the level of Tyr204/187-phosphorylated ERK1/2 at 0 h following chronic ECS (∗p < 0.05) but has no effect on total GluN2B expression in the hippocampus.
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fig4: A single ECS and chronic ECS differently alter Tyr204/187-phosphorylation of ERK1/2 in the hippocampus. Immunoblot analysis for the phosphorylation of ERK1/2 at Tyr204/187 (Y204/187) and total ERK1/2 expression in the hippocampal crude membrane (P2) fraction following a single ECS (n = 5 rats per time point) (a) and chronic ECS (n = 6 rats per time point) (b). The ratio of the Tyr204/187-phosphorylated ERK1/2 band intensity over the β-actin band intensity (top graphs) and the ratio of total ERK1/2 band intensity over the β-actin band intensity (bottom graphs) were calculated per each time point and normalized to that of “no seizure” (NS) sham group. Data shown represent the mean band intensity ± SEM. (a) A single ECS transiently decreases the level of Tyr204/187-phosphorylated ERK1/2 in the hippocampus at 48 h (###p < 0.005, t-test) and total ERK1/2 expression at 72–96 h (∗p < 0.05) following a single ECS. (b) Chronic ECS significantly increases the level of Tyr204/187-phosphorylated ERK1/2 at 0 h following chronic ECS (∗p < 0.05) but has no effect on total GluN2B expression in the hippocampus.

Mentions: All data shown represent the mean value ± SEM. The number of rats is expressed as sample size n. Statistical analyses were performed with either Microsoft Excel or Origin (version 8.5; OriginLab). For most data sets, a priori value (∗p) < 0.05 was considered statistically significant following one-way ANOVA and post hoc ANOVA tests (Fisher's test). For Figure 1(a), Student's t-test was used due to low sample size (n = 2-3 rats per postnatal day). For the statistical analysis of the levels of Tyr204/187-phosphorylated ERK1/2 in Figure 4(a) and Aβ in Figure 5(a), Student's t-test was used because one-way ANOVA and post hoc ANOVA tests (Fisher's test) were not adequate to perform in the data sets that contained a large variability when 5 sets of independent experiments for a single ECS were compared. For Student's t-test, a priori value (#p) < 0.05 was considered statistically significant.


Seizure-Induced Regulations of Amyloid-β, STEP61, and STEP61 Substrates Involved in Hippocampal Synaptic Plasticity.

Jang SS, Royston SE, Lee G, Wang S, Chung HJ - Neural Plast. (2016)

A single ECS and chronic ECS differently alter Tyr204/187-phosphorylation of ERK1/2 in the hippocampus. Immunoblot analysis for the phosphorylation of ERK1/2 at Tyr204/187 (Y204/187) and total ERK1/2 expression in the hippocampal crude membrane (P2) fraction following a single ECS (n = 5 rats per time point) (a) and chronic ECS (n = 6 rats per time point) (b). The ratio of the Tyr204/187-phosphorylated ERK1/2 band intensity over the β-actin band intensity (top graphs) and the ratio of total ERK1/2 band intensity over the β-actin band intensity (bottom graphs) were calculated per each time point and normalized to that of “no seizure” (NS) sham group. Data shown represent the mean band intensity ± SEM. (a) A single ECS transiently decreases the level of Tyr204/187-phosphorylated ERK1/2 in the hippocampus at 48 h (###p < 0.005, t-test) and total ERK1/2 expression at 72–96 h (∗p < 0.05) following a single ECS. (b) Chronic ECS significantly increases the level of Tyr204/187-phosphorylated ERK1/2 at 0 h following chronic ECS (∗p < 0.05) but has no effect on total GluN2B expression in the hippocampus.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig4: A single ECS and chronic ECS differently alter Tyr204/187-phosphorylation of ERK1/2 in the hippocampus. Immunoblot analysis for the phosphorylation of ERK1/2 at Tyr204/187 (Y204/187) and total ERK1/2 expression in the hippocampal crude membrane (P2) fraction following a single ECS (n = 5 rats per time point) (a) and chronic ECS (n = 6 rats per time point) (b). The ratio of the Tyr204/187-phosphorylated ERK1/2 band intensity over the β-actin band intensity (top graphs) and the ratio of total ERK1/2 band intensity over the β-actin band intensity (bottom graphs) were calculated per each time point and normalized to that of “no seizure” (NS) sham group. Data shown represent the mean band intensity ± SEM. (a) A single ECS transiently decreases the level of Tyr204/187-phosphorylated ERK1/2 in the hippocampus at 48 h (###p < 0.005, t-test) and total ERK1/2 expression at 72–96 h (∗p < 0.05) following a single ECS. (b) Chronic ECS significantly increases the level of Tyr204/187-phosphorylated ERK1/2 at 0 h following chronic ECS (∗p < 0.05) but has no effect on total GluN2B expression in the hippocampus.
Mentions: All data shown represent the mean value ± SEM. The number of rats is expressed as sample size n. Statistical analyses were performed with either Microsoft Excel or Origin (version 8.5; OriginLab). For most data sets, a priori value (∗p) < 0.05 was considered statistically significant following one-way ANOVA and post hoc ANOVA tests (Fisher's test). For Figure 1(a), Student's t-test was used due to low sample size (n = 2-3 rats per postnatal day). For the statistical analysis of the levels of Tyr204/187-phosphorylated ERK1/2 in Figure 4(a) and Aβ in Figure 5(a), Student's t-test was used because one-way ANOVA and post hoc ANOVA tests (Fisher's test) were not adequate to perform in the data sets that contained a large variability when 5 sets of independent experiments for a single ECS were compared. For Student's t-test, a priori value (#p) < 0.05 was considered statistically significant.

Bottom Line: Pathologic accumulation of soluble amyloid-β (Aβ) oligomers impairs synaptic plasticity and causes epileptic seizures, both of which contribute to cognitive dysfunction in AD.Here we show that a single episode of electroconvulsive seizures (ECS) increased protein expression of membrane-associated STriatal-Enriched protein tyrosine Phosphatase (STEP61) and decreased tyrosine-phosphorylation of its substrates N-methyl D-aspartate receptor (NMDAR) subunit GluN2B and extracellular signal regulated kinase 1/2 (ERK1/2) in the rat hippocampus at 2 days following a single ECS.Interestingly, a significant decrease in ERK1/2 expression and an increase in APP and Aβ levels were observed at 3-4 days following a single ECS when STEP61 level returned to the baseline.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Neuroscience Program, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.

ABSTRACT
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline. Pathologic accumulation of soluble amyloid-β (Aβ) oligomers impairs synaptic plasticity and causes epileptic seizures, both of which contribute to cognitive dysfunction in AD. However, whether seizures could regulate Aβ-induced synaptic weakening remains unclear. Here we show that a single episode of electroconvulsive seizures (ECS) increased protein expression of membrane-associated STriatal-Enriched protein tyrosine Phosphatase (STEP61) and decreased tyrosine-phosphorylation of its substrates N-methyl D-aspartate receptor (NMDAR) subunit GluN2B and extracellular signal regulated kinase 1/2 (ERK1/2) in the rat hippocampus at 2 days following a single ECS. Interestingly, a significant decrease in ERK1/2 expression and an increase in APP and Aβ levels were observed at 3-4 days following a single ECS when STEP61 level returned to the baseline. Given that pathologic levels of Aβ increase STEP61 activity and STEP61-mediated dephosphorylation of GluN2B and ERK1/2 leads to NMDAR internalization and ERK1/2 inactivation, we propose that upregulation of STEP61 and downregulation of GluN2B and ERK1/2 phosphorylation mediate compensatory weakening of synaptic strength in response to acute enhancement of hippocampal network activity, whereas delayed decrease in ERK1/2 expression and increase in APP and Aβ expression may contribute to the maintenance of this synaptic weakening.

No MeSH data available.


Related in: MedlinePlus