Objective Shp2 is member of the Src homology-2 (SH2)-containing protein tyrosine phosphatase (PTPs) subfamily.It is widely expressed, with relatively high levels in the brain and heart.Accumulating evidence suggests a critical role of Shp2 in cellular signaling and development of the CNS, but the role of Shp2 in modulating synaptic function is unclear.As we known, mutations in SHP2 gene cause clinically similar but distinctive disorders, LEOPARD syndromes (LS) and Noonan syndromes (NS).Strikingly, most of these patients have a mild mental retard.Otherwise, Shp2 in postsynaptic density protein complex physically associates with NR2B subunit, but the physiological function is unknown.This study is to investigate the role of Shp2 in fear memory and synaptic function.Methods Slice electrophysiological experiment and behavior test were done in both wildtype and forebrain specific Shp2 knockout mouse.Molecular biology, co-immunoprecipition assay, Western blot and cell culture were used in this study.Results (1) Our data suggest that the fear memory reconsolidation is impaired in the Shp2 knockout mouse; (2) The paired pulse facilitation (PPF) of Shp2 knockout mouse is similar to that of wildtype mouse, but the LTP induction is impaired in Shp2 knockout mouse; (3) Identified a motif of NR2B C-terminus is specifically interacted with Shp2; (4) NMDAR decay time of Shp2 knockout mouse is significantly faster than that of wildtype mouse.Conclusion Shp2 is involved in fear memory by regulating NMDAR mediated synaptic function in CNS.