The down-regulation of tyrosine phosphatase SHP2 activity is involved in the removal of surface AMPA receptors in long term depression.

Hebbian-type synaptic plasticity which includes long term potentiation (LTP) and long term depression (LTD), is the main cellular mechanism underlying learning and memory. Effective activity and synaptic content of tyrosine phosphatase SHP2 are required for AMPA receptor trafficking during LTP. However, the role of SHP2 in LTD has not been fully elucidated. This study shows that the phosphorylation level of SHP2 at Y542 decreased after LTD induction either in hippocampal cultures or acute CA1 mini slices. This change occurred at least 10 min after LTD induction and was alleviated by administration of NMDA receptor antagonist, APV. Furthermore, the SHP2 mutant (D61G), found in Noonan syndrome patients, prevented the removal of surface AMPA receptors during chemical-induced LTD on cultured hippocampal neurons. The results revealed a molecular basis of regulatory role of SHP2 in long term depression, thus expands our understanding of the SHP2 function in learning and memory.