Regulation of STEP61 and tyrosine-phosphorylation of NMDA and AMPA receptors during homeostatic synaptic plasticity.

Sung-Soo Jang,Seungbae Lee,Paul J Lombroso,Kwan Young Lee,John P Cavaretta,Sara E Royston,Jian Xu,Max O Vest,Han Gil Jeong,Hee Jung Chung

doi:10.1186/s13041-015-0148-4

Abstract

BackgroundSustained changes in network activity cause homeostatic synaptic plasticity in part by altering the postsynaptic accumulation of N-methyl-D-aspartate receptors (NMDAR) and α-amino-3-hydroxyle-5-methyl-4-isoxazolepropionic acid receptors (AMPAR), which are primary mediators of excitatory synaptic transmission. A key trafficking modulator of NMDAR and AMPAR is STriatal-Enriched protein tyrosine Phosphatase (STEP61) that opposes synaptic strengthening through dephosphorylation of NMDAR subunit GluN2B and AMPAR subunit GluA2. However, the role of STEP61 in homeostatic synaptic plasticity is unknown.FindingsWe demonstrate here that prolonged activity blockade leads to synaptic scaling, and a concurrent decrease in STEP61 level and activity in rat dissociated hippocampal cultured neurons. Consistent with STEP61 reduction, prolonged activity blockade enhances the tyrosine phosphorylation of GluN2B and GluA2 whereas increasing STEP61 activity blocks this regulation and synaptic scaling. Conversely, prolonged activity enhancement increases STEP61 level and activity, and reduces the tyrosine phosphorylation and level of GluN2B as well as GluA2 expression in a STEP61–dependent manner.ConclusionsGiven that STEP61-mediated dephosphorylation of GluN2B and GluA2 leads to their internalization, our results collectively suggest that activity-dependent regulation of STEP61 and its substrates GluN2B and GluA2 may contribute to homeostatic stabilization of excitatory synapses.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-015-0148-4) contains supplementary material, which is available to authorized users.

Highlights

Sustained changes in network activity cause homeostatic synaptic plasticity in part by altering the postsynaptic accumulation of N-methyl-D-aspartate receptors (NMDAR) and α-amino-3-hydroxyle-5-methyl-4isoxazolepropionic acid receptors (AMPAR), which are primary mediators of excitatory synaptic transmission
Given that STEP61-mediated dephosphorylation of GluN2B and GluA2 leads to their internalization, our results collectively suggest that activity-dependent regulation of STEP61 and its substrates GluN2B and GluA2 may contribute to homeostatic stabilization of excitatory synapses
Prolonged alterations of hippocampal network activity regulate STEP61 level and activity Prolonged blockade of network activity for 48 h with the sodium channel blocker tetrodotoxin (TTX) induced synaptic scaling in dissociated hippocampal cultured neurons as demonstrated previously [11, 12] (Fig. 1a–d), and reduced STEP61 mRNA and protein expression compared to CTL treatment (Fig. 1e, f)

Summary

Introduction

Sustained changes in network activity cause homeostatic synaptic plasticity in part by altering the postsynaptic accumulation of N-methyl-D-aspartate receptors (NMDAR) and α-amino-3-hydroxyle-5-methyl-4isoxazolepropionic acid receptors (AMPAR), which are primary mediators of excitatory synaptic transmission. A key trafficking modulator of NMDAR and AMPAR is STriatal-Enriched protein tyrosine Phosphatase (STEP61) that opposes synaptic strengthening through dephosphorylation of NMDAR subunit GluN2B and AMPAR subunit GluA2. The role of STEP61 in homeostatic synaptic plasticity is unknown

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