Abstract
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.
Highlights
Src Homology 2 domain– containing phosphotyrosine phosphatase 2 (Shp2) functions in synaptic plasticity, learning, and memory
These results reveal that the activity of Shp2 is bidirectionally regulated during synaptic scaling
We focused on the molecular role of Shp2 in homeostatic plasticity and uncovered a novel role of Shp2 in synaptic upscaling-mediated changes of surface GluA1 by pharmacological and genetic approaches
Summary
To explore whether the phosphorylation level of Tyr542 in Shp (hereafter referred to as the Tyr(P)542 level) is regulated during synaptic scaling, we treated cultured rat hippocampal neurons with bicuculline (Bic) or tetrodotoxin (TTX) for 48 h to induce synaptic scaling down or scaling up, as reported previously [21]. Hippocampal neurons transfected with Shp WT showed increased surface GluA1 expression after TTX treatment, whereas the increase was not observed in neurons transfected with the Shp C459S mutation after 48 h of TTX (Fig. 4, A and B; TTX for Shp WT, 1.429 Ϯ 0.070; control for Shp C459S, 1.052 Ϯ 0.029; TTX for Shp C459S, 1.028 Ϯ 0.031) These data suggest that constitutive inactivation of Shp impairs surface GluA1 up-regulation in synaptic upscaling. In line with our results from Shp inhibitors and the Shp2-inactive mutant, hippocampal neurons infected with AAV-GFP displayed increased surface GluA1 expression after 48-h TTX treatment, whereas surface GluA1 expression failed to elevate in neurons infected with AAV-Cre after 48 h of TTX (Fig. 4, E and F; TTX for AAV-GFP, 1.334 Ϯ 0.039; control for AAV-Cre, 0.990 Ϯ 0.038; TTX for AAV-Cre, 1.093 Ϯ 0.046) These data suggest that loss of Shp function occludes surface GluA1 up-regulation during synaptic upscaling
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