Regulation of STEP(61) and tyrosine-phosphorylation of NMDA and AMPA receptors during homeostatic synaptic plasticity

BACKGROUND: 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-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 (STEP(61)) that opposes synaptic strengthening through dephosphorylation of NMDAR subunit GluN2B and AMPAR subunit GluA2. However, the role of STEP(61) in homeostatic synaptic plasticity is unknown. FINDINGS: We demonstrate here that prolonged activity blockade leads to synaptic scaling, and a concurrent decrease in STEP(61) level and activity in rat dissociated hippocampal cultured neurons. Consistent with STEP(61) reduction, prolonged activity blockade enhances the tyrosine phosphorylation of GluN2B and GluA2 whereas increasing STEP(61) activity blocks this regulation and synaptic scaling. Conversely, prolonged activity enhancement increases STEP(61) level and activity, and reduces the tyrosine phosphorylation and level of GluN2B as well as GluA2 expression in a STEP(61)–dependent manner. CONCLUSIONS: Given that STEP(61)-mediated dephosphorylation of GluN2B and GluA2 leads to their internalization, our results collectively suggest that activity-dependent regulation of STEP(61) and its substrates GluN2B and GluA2 may contribute to homeostatic stabilization of excitatory synapses. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13041-015-0148-4) contains supplementary material, which is available to authorized users.