Src homology 2 domain-containing phosphotyrosine phosphatase 2 (Shp2) controls surface GluA1 protein in synaptic homeostasis.

Src Homology 2 domain-containing phosphotyrosine phosphatase 2 (Shp2) functions in synaptic plasticity, learning, and memory. However, the precise mechanisms by which this multifunctional protein contributes to synaptic function remains largely unknown. Homeostatic plasticity may be viewed as a process of bidirectional synaptic scaling, up or down. Through this process, neuronal circuitry stability is maintained so that changes in synaptic strength may be preserved under changing conditions. A better understanding of these processes is needed. In this regard, we report that phosphorylation of Shp2 at tyrosine 542 and its translocation to the postsynaptic compartment are integral processes in synaptic scaling. Furthermore, we show, using both pharmacological and genetic approaches, that Shp2 phosphatase activity is critical to the regulation of Ser(P)845 GluA1 and surface expression of this AMPA receptor subunit during synaptic scaling. Thus, Shp2 may contribute meaningfully to synaptic homeostasis.