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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 increases the level of Tyr876-phosphorylated GluA2 in the hippocampus. Immunoblot analysis for phosphorylation of GluA2 at Tyr876 (Y876) or 3Tyr (3Y: Tyr869, Tyr873, and Tyr876) and total GluA2 expression in the hippocampal crude membrane (P2) fraction following a single ECS (n = 5 rats per time point) (a–c) and chronic ECS (n = 5 rats for 72 h time point and n = 6 rats per all other time points) (d–f). The ratio of the phosphorylated GluA2 band intensity over the β-actin band intensity (a-b, d-e) and the ratio of total GluA2 band intensity over the β-actin band intensity (c, f) 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–c) A single ECS increases the level of Tyr876-phosphorylated GluA2 at 96 h time point ((b) ∗p < 0.05) but does not alter the level of 3Tyr-phosphorylated GluA2 and total GluA2. (d–f) Chronic ECS does not change Tyr-phosphorylation of GluA2 (d-e) and total GluA2 expression (f).
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fig3: A single ECS but not chronic ECS increases the level of Tyr876-phosphorylated GluA2 in the hippocampus. Immunoblot analysis for phosphorylation of GluA2 at Tyr876 (Y876) or 3Tyr (3Y: Tyr869, Tyr873, and Tyr876) and total GluA2 expression in the hippocampal crude membrane (P2) fraction following a single ECS (n = 5 rats per time point) (a–c) and chronic ECS (n = 5 rats for 72 h time point and n = 6 rats per all other time points) (d–f). The ratio of the phosphorylated GluA2 band intensity over the β-actin band intensity (a-b, d-e) and the ratio of total GluA2 band intensity over the β-actin band intensity (c, f) 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–c) A single ECS increases the level of Tyr876-phosphorylated GluA2 at 96 h time point ((b) ∗p < 0.05) but does not alter the level of 3Tyr-phosphorylated GluA2 and total GluA2. (d–f) Chronic ECS does not change Tyr-phosphorylation of GluA2 (d-e) and total GluA2 expression (f).

Mentions: STEP61 reduces Tyr-phosphorylation of AMPAR subunit GluA2 and mediates AMPAR internalization upon acute stimulation of group 1 metabotropic glutamate receptors (mGluR) and application of Aβ [24, 26]. Although it is unclear which specific Tyr residue (s) in GluA2 is directly dephosphorylated by STEP61, AMPAR internalization is reported to involve dephosphorylation of Tyr869, Tyr873, and Tyr876 (3Tyr) within the intracellular GluA2 C-terminal region (GluA-p3Y) [43]. We therefore hypothesized that a single ECS-induced increase in STEP61 expression would decrease the level of 3Tyr-phosphorylated GluA2 as well as Tyr876-phosphorylated GluA2 in the hippocampus. There was an increasing trend for the level of 3Tyr-phosphorylated GluA2 over the course of 96 h following a single ECS compared to NS control, although this increase did not reach statistical significance due to a large standard deviation (Figure 3(a), Supplemental Figure  4). To our surprise, the level of Tyr876-phosphorylated GluA2 was unaltered at 48 h following a single ECS (Figure 3(b), Supplemental Figure  4, 77.8 ± 21.4% of NS, p > 0.05) when STEP61 expression was significantly increased compared to NS control (Figure 1(d)). Instead, the level of Tyr876-phosphorylated GluA2 was significantly increased by 2-fold at 96 h following a single ECS (Figure 3(b), 178.6 ± 27.5% of NS, p < 0.05) when STEP61 expression was similar to that of NS control (Figure 1(d)). A single ECS had no effect on total GluA2 expression (Figure 3(c), Supplemental Figure  4). Chronic ECS did not alter the levels of 3Tyr-phosphorylated GluA2, Tyr876-phosphorylated GluA2, and total GluA2 (Figures 3(d)–3(f), Supplemental Figure  5). These data indicate that a single ECS regulates Tyr876-phosphorylation of GluA2 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 increases the level of Tyr876-phosphorylated GluA2 in the hippocampus. Immunoblot analysis for phosphorylation of GluA2 at Tyr876 (Y876) or 3Tyr (3Y: Tyr869, Tyr873, and Tyr876) and total GluA2 expression in the hippocampal crude membrane (P2) fraction following a single ECS (n = 5 rats per time point) (a–c) and chronic ECS (n = 5 rats for 72 h time point and n = 6 rats per all other time points) (d–f). The ratio of the phosphorylated GluA2 band intensity over the β-actin band intensity (a-b, d-e) and the ratio of total GluA2 band intensity over the β-actin band intensity (c, f) 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–c) A single ECS increases the level of Tyr876-phosphorylated GluA2 at 96 h time point ((b) ∗p < 0.05) but does not alter the level of 3Tyr-phosphorylated GluA2 and total GluA2. (d–f) Chronic ECS does not change Tyr-phosphorylation of GluA2 (d-e) and total GluA2 expression (f).
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig3: A single ECS but not chronic ECS increases the level of Tyr876-phosphorylated GluA2 in the hippocampus. Immunoblot analysis for phosphorylation of GluA2 at Tyr876 (Y876) or 3Tyr (3Y: Tyr869, Tyr873, and Tyr876) and total GluA2 expression in the hippocampal crude membrane (P2) fraction following a single ECS (n = 5 rats per time point) (a–c) and chronic ECS (n = 5 rats for 72 h time point and n = 6 rats per all other time points) (d–f). The ratio of the phosphorylated GluA2 band intensity over the β-actin band intensity (a-b, d-e) and the ratio of total GluA2 band intensity over the β-actin band intensity (c, f) 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–c) A single ECS increases the level of Tyr876-phosphorylated GluA2 at 96 h time point ((b) ∗p < 0.05) but does not alter the level of 3Tyr-phosphorylated GluA2 and total GluA2. (d–f) Chronic ECS does not change Tyr-phosphorylation of GluA2 (d-e) and total GluA2 expression (f).
Mentions: STEP61 reduces Tyr-phosphorylation of AMPAR subunit GluA2 and mediates AMPAR internalization upon acute stimulation of group 1 metabotropic glutamate receptors (mGluR) and application of Aβ [24, 26]. Although it is unclear which specific Tyr residue (s) in GluA2 is directly dephosphorylated by STEP61, AMPAR internalization is reported to involve dephosphorylation of Tyr869, Tyr873, and Tyr876 (3Tyr) within the intracellular GluA2 C-terminal region (GluA-p3Y) [43]. We therefore hypothesized that a single ECS-induced increase in STEP61 expression would decrease the level of 3Tyr-phosphorylated GluA2 as well as Tyr876-phosphorylated GluA2 in the hippocampus. There was an increasing trend for the level of 3Tyr-phosphorylated GluA2 over the course of 96 h following a single ECS compared to NS control, although this increase did not reach statistical significance due to a large standard deviation (Figure 3(a), Supplemental Figure  4). To our surprise, the level of Tyr876-phosphorylated GluA2 was unaltered at 48 h following a single ECS (Figure 3(b), Supplemental Figure  4, 77.8 ± 21.4% of NS, p > 0.05) when STEP61 expression was significantly increased compared to NS control (Figure 1(d)). Instead, the level of Tyr876-phosphorylated GluA2 was significantly increased by 2-fold at 96 h following a single ECS (Figure 3(b), 178.6 ± 27.5% of NS, p < 0.05) when STEP61 expression was similar to that of NS control (Figure 1(d)). A single ECS had no effect on total GluA2 expression (Figure 3(c), Supplemental Figure  4). Chronic ECS did not alter the levels of 3Tyr-phosphorylated GluA2, Tyr876-phosphorylated GluA2, and total GluA2 (Figures 3(d)–3(f), Supplemental Figure  5). These data indicate that a single ECS regulates Tyr876-phosphorylation of GluA2 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