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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 but not chronic ECS transiently decreases the level of Tyr1472-phosphorylated GluN2B in the hippocampus. Immunoblot analysis for the phosphorylation of GluN2B at Tyr1472 (Y1472) and total GluN2B 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 Tyr1472-phosphorylated GluN2B band intensity over the β-actin band intensity (top graphs) and the ratio of total GluN2B 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 Tyr1472-phosphorylated GluN2B in the hippocampus at 48 h (∗∗∗p < 0.005) and 72 h (∗p < 0.05) following a single ECS. (b) Chronic ECS significantly decreases total GluN2B expression over the time course of 96 h in the hippocampus (∗p < 0.05, ∗∗p < 0.01, and ∗∗∗p < 0.005).
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fig2: A single ECS but not chronic ECS transiently decreases the level of Tyr1472-phosphorylated GluN2B in the hippocampus. Immunoblot analysis for the phosphorylation of GluN2B at Tyr1472 (Y1472) and total GluN2B 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 Tyr1472-phosphorylated GluN2B band intensity over the β-actin band intensity (top graphs) and the ratio of total GluN2B 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 Tyr1472-phosphorylated GluN2B in the hippocampus at 48 h (∗∗∗p < 0.005) and 72 h (∗p < 0.05) following a single ECS. (b) Chronic ECS significantly decreases total GluN2B expression over the time course of 96 h in the hippocampus (∗p < 0.05, ∗∗p < 0.01, and ∗∗∗p < 0.005).

Mentions: Enriched in the postsynaptic density, STEP61 dephosphorylates NMDAR subunit GluN2B at Tyr1472, leading to internalization of GluN2B-containing NMDAR [11, 22, 24, 25, 41, 42]. We hypothesized that a single ECS-induced increase in STEP61 expression would decrease Tyr1472-phosphorylation of GluN2B in the hippocampus. Consistent with our hypothesis, western blot analysis of hippocampal P2 lysates revealed a significant reduction in the level of Tyr1472-phosphorylated GluN2B (GluN2B-pY1472) compared to NS group from 48 to 72 h following a single ECS (Supplemental Figure  3), with the most reduction seen at 48 h (Figure 2(a), 27.0 ± 12.7% of NS, p < 0.005) when STEP61 expression was transiently enhanced (Figure 1(d)). The level of Tyr1472-phosphorylated GluN2B was returned to the level of NS group by 96 h after a single ECS (Figure 2(a), Supplemental Figure  3) when elevated STEP61 level decreased back to the level of NS group (Figure 1(d)). Total GluN2B expression did not change following a single ECS (Figure 2(a), Supplemental Figure  3). Although chronic ECS did not alter the level of Tyr1472-phosphorylated GluN2B compared to NS control (Figure 2(b), Supplemental Figure  3), there was a modest but significant reduction in total GluN2B expression from 0 h to 24 h and 72 h to 96 h following chronic ECS compared to NS control (Figure 2(b), 96 h: 63.8 ± 6.7%, p < 0.005). These data indicate that a single ECS transiently reduced Tyr1472-phosphorylation of GluN2B whereas chronic ECS persistently reduced total GluN2B expression in the hippocampus.


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 but not chronic ECS transiently decreases the level of Tyr1472-phosphorylated GluN2B in the hippocampus. Immunoblot analysis for the phosphorylation of GluN2B at Tyr1472 (Y1472) and total GluN2B 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 Tyr1472-phosphorylated GluN2B band intensity over the β-actin band intensity (top graphs) and the ratio of total GluN2B 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 Tyr1472-phosphorylated GluN2B in the hippocampus at 48 h (∗∗∗p < 0.005) and 72 h (∗p < 0.05) following a single ECS. (b) Chronic ECS significantly decreases total GluN2B expression over the time course of 96 h in the hippocampus (∗p < 0.05, ∗∗p < 0.01, and ∗∗∗p < 0.005).
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig2: A single ECS but not chronic ECS transiently decreases the level of Tyr1472-phosphorylated GluN2B in the hippocampus. Immunoblot analysis for the phosphorylation of GluN2B at Tyr1472 (Y1472) and total GluN2B 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 Tyr1472-phosphorylated GluN2B band intensity over the β-actin band intensity (top graphs) and the ratio of total GluN2B 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 Tyr1472-phosphorylated GluN2B in the hippocampus at 48 h (∗∗∗p < 0.005) and 72 h (∗p < 0.05) following a single ECS. (b) Chronic ECS significantly decreases total GluN2B expression over the time course of 96 h in the hippocampus (∗p < 0.05, ∗∗p < 0.01, and ∗∗∗p < 0.005).
Mentions: Enriched in the postsynaptic density, STEP61 dephosphorylates NMDAR subunit GluN2B at Tyr1472, leading to internalization of GluN2B-containing NMDAR [11, 22, 24, 25, 41, 42]. We hypothesized that a single ECS-induced increase in STEP61 expression would decrease Tyr1472-phosphorylation of GluN2B in the hippocampus. Consistent with our hypothesis, western blot analysis of hippocampal P2 lysates revealed a significant reduction in the level of Tyr1472-phosphorylated GluN2B (GluN2B-pY1472) compared to NS group from 48 to 72 h following a single ECS (Supplemental Figure  3), with the most reduction seen at 48 h (Figure 2(a), 27.0 ± 12.7% of NS, p < 0.005) when STEP61 expression was transiently enhanced (Figure 1(d)). The level of Tyr1472-phosphorylated GluN2B was returned to the level of NS group by 96 h after a single ECS (Figure 2(a), Supplemental Figure  3) when elevated STEP61 level decreased back to the level of NS group (Figure 1(d)). Total GluN2B expression did not change following a single ECS (Figure 2(a), Supplemental Figure  3). Although chronic ECS did not alter the level of Tyr1472-phosphorylated GluN2B compared to NS control (Figure 2(b), Supplemental Figure  3), there was a modest but significant reduction in total GluN2B expression from 0 h to 24 h and 72 h to 96 h following chronic ECS compared to NS control (Figure 2(b), 96 h: 63.8 ± 6.7%, p < 0.005). These data indicate that a single ECS transiently reduced Tyr1472-phosphorylation of GluN2B whereas chronic ECS persistently reduced total GluN2B expression in the hippocampus.

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