Regulation of STEP₆₁ 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 (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. Findings: We 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. Conclusions: 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.