Regulation And Function Of Shp2 Activity In Synaptic Plasticity

Efficiency of excitatory neurotransmission changs with neuron activity, which is the basis of plasticity of neuronal networks and widely accepted as the primary cellular mechanism of cognitive functions such as learning and memory. Long-term potentiation (LTP) and its opposing effect, long-term depression (LTD) have been widely accepted as two cellular mechanism underlying synaptic plasticity. LTP is expressed by a synapse-specific increase in the number of AMPA receptors at postsynaptic sites while LTD presents its contrast effect that manifests decrease in the number of AMPA receptors. At glutamatergic synapses, protein phosphorylation impact on the regulation of AMPA receptor-mediated excitatory neurotransmission. Meanwhile, phosphatases have an equally dynamic and critical role with activity-dependent activation in synaptic plasticity. Recently, convegnet evidences indicate that Src homology 2 domain containing phosphotyrosine phosphatase 2 (Shp2), a ubiquitously expressed phosphatase serves a fundamental role in synaptic plasticity and memory. Both gain-of-function and loss-of-function mutation in Shp2 cause developmental disorders associate with mental retardation. In addition, genetic manipulation, e.g. knock-in mice with Noonan syndrome (NS) mutation of Shp2, and ablation of Shp2, no matter in Drosophila or rodents, both reveal that Shp2 is profoundly involved in synaptic plasticity and memory. However, the exact mechanism underling Shp2 function in synaptic plasticity and memory still remains elusive. Here, we investigted the regulation of Shp2 activity in hippocampal synaptic plasticity. We first examined the expression profile of Shp2 and found that phosphorylated Shp2 at Y542 (pY542) increased during development, we also found that pY542 level exhibited relatively much higher in PSD fraction and Shp2 was recruited into postsynaptic site during LTP. Then, we found up-regulated Shp2 activity during LTP while down-regulation during LTD. Notably, these two process were NMD A receptor dependent. We also found increased pY542 level after contextual fear conditioning. Furthermore, we provided evidence that the phosphatase activity of Shp2 was critical for LTP by using Shp2 specific inhibitor (NSC87877) which suppressed Shp2 phosphatase activity. Our results of AAV-Cre mediated KO of Shp2 in cultured hippocampal neurons derived from Shp2flox/flox mice also demonstrated that Shp2 function was required for AMPA receptor delivery in LTP. Collectively, our results revealed that the activity of Shp2 was regulated bidirectionally and increased activity of Shp2 is required for synaptic plasticity which broadening our understanding and supplement the list of function of Shp2 in cognitive function.