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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

Model by which seizure-induced changes in Aβ, STEP61, and Tyr-phosphorylation of STEP61 lead to synaptic weakening in the hippocampus. A single ECS increases STEP61 expression and decreases Tyr-phosphorylation of NMDAR subunit GluN2B and ERK1/2 in the hippocampus at 48 h time point, leading to synaptic weakening via NMDAR internalization and ERK1/2 inactivation. A delayed decrease in ERK1/2 expression as well as a delayed enhancement of APP and Aβ expression at 72–96 h following a single ECS maintains this synaptic weakening. Chronic ECS-induced increase in APP expression and Aβ production as well as persistent decrease in total GluN2B level leads to synaptic weakening.
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fig6: Model by which seizure-induced changes in Aβ, STEP61, and Tyr-phosphorylation of STEP61 lead to synaptic weakening in the hippocampus. A single ECS increases STEP61 expression and decreases Tyr-phosphorylation of NMDAR subunit GluN2B and ERK1/2 in the hippocampus at 48 h time point, leading to synaptic weakening via NMDAR internalization and ERK1/2 inactivation. A delayed decrease in ERK1/2 expression as well as a delayed enhancement of APP and Aβ expression at 72–96 h following a single ECS maintains this synaptic weakening. Chronic ECS-induced increase in APP expression and Aβ production as well as persistent decrease in total GluN2B level leads to synaptic weakening.

Mentions: We show that STEP61 level was markedly increased in rat hippocampus at 48 h after a single induction of ECS (Figure 1(d)), which induces global elevation of hippocampal neuronal activity [33]. Consistent with this increase in STEP61 expression, the level of Tyr1472-phosphorylated GluN2B was reduced at 48–72 h following a single ECS without altering total GluN2B expression (Figure 2(a)). Considering that STEP61-mediated dephosphorylation of GluN2B leads to internalization of GluN2B-containing NMDARs [11], upregulation of STEP61 (Figure 1(d)) may serve as a compensatory mechanism to reduce surface density of NMDARs in the hippocampus in response to seizures (Figure 6). Consistent with the previous report on ECS-induced decreases in PSD-95 and GluN2A/B expression [50], chronic ECS caused a persistent decrease in total GluN2B expression over the course of 96 h following chronic ECS (Figure 2(b)). NMDAR activation requires coincident binding of glutamate and membrane depolarization produced by opening of AMPARs [51]. Hence, although chronic ECS did not alter GluA2 level (Figure 3(f)), a persistent decline in GluN2B expression (Figure 2(b)) could facilitate synaptic weakening in response to repetitive seizures.


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)

Model by which seizure-induced changes in Aβ, STEP61, and Tyr-phosphorylation of STEP61 lead to synaptic weakening in the hippocampus. A single ECS increases STEP61 expression and decreases Tyr-phosphorylation of NMDAR subunit GluN2B and ERK1/2 in the hippocampus at 48 h time point, leading to synaptic weakening via NMDAR internalization and ERK1/2 inactivation. A delayed decrease in ERK1/2 expression as well as a delayed enhancement of APP and Aβ expression at 72–96 h following a single ECS maintains this synaptic weakening. Chronic ECS-induced increase in APP expression and Aβ production as well as persistent decrease in total GluN2B level leads to synaptic weakening.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig6: Model by which seizure-induced changes in Aβ, STEP61, and Tyr-phosphorylation of STEP61 lead to synaptic weakening in the hippocampus. A single ECS increases STEP61 expression and decreases Tyr-phosphorylation of NMDAR subunit GluN2B and ERK1/2 in the hippocampus at 48 h time point, leading to synaptic weakening via NMDAR internalization and ERK1/2 inactivation. A delayed decrease in ERK1/2 expression as well as a delayed enhancement of APP and Aβ expression at 72–96 h following a single ECS maintains this synaptic weakening. Chronic ECS-induced increase in APP expression and Aβ production as well as persistent decrease in total GluN2B level leads to synaptic weakening.
Mentions: We show that STEP61 level was markedly increased in rat hippocampus at 48 h after a single induction of ECS (Figure 1(d)), which induces global elevation of hippocampal neuronal activity [33]. Consistent with this increase in STEP61 expression, the level of Tyr1472-phosphorylated GluN2B was reduced at 48–72 h following a single ECS without altering total GluN2B expression (Figure 2(a)). Considering that STEP61-mediated dephosphorylation of GluN2B leads to internalization of GluN2B-containing NMDARs [11], upregulation of STEP61 (Figure 1(d)) may serve as a compensatory mechanism to reduce surface density of NMDARs in the hippocampus in response to seizures (Figure 6). Consistent with the previous report on ECS-induced decreases in PSD-95 and GluN2A/B expression [50], chronic ECS caused a persistent decrease in total GluN2B expression over the course of 96 h following chronic ECS (Figure 2(b)). NMDAR activation requires coincident binding of glutamate and membrane depolarization produced by opening of AMPARs [51]. Hence, although chronic ECS did not alter GluA2 level (Figure 3(f)), a persistent decline in GluN2B expression (Figure 2(b)) could facilitate synaptic weakening in response to repetitive seizures.

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