Shp2, Src homology 2 domain-containing protein tyrosine phosphatase 2, is crucial for cell growth and differentiation. However, Shp2 is also expressed in post-mitotic neurons, and mutations of Shp2 are associated with a clinical condition of mental retardation. To investigate the roles of Shp2 in the adult brain, we selectively deleted Shp2 gene in post-mitotic neurons in conditional knockout (cKO) mice that was obtained by crossing CaMKII-Cre transgenic mice with Shp2-floxed mice. Shp2 cKO mice showed normal brain structure but exhibited abnormal behaviors including hyperactivity. In the brain of Shp2 cKO mice, novelty-induced expression of immediate early genes was significantly attenuated, suggesting a reduction of neuronal excitability. Ablation of Shp2 significantly increased high K⁺-induced activation of MAPK in both cultured neurons and synaptosomes, while BDNF-induced activation of MAPK was significantly reduced in Shp2-knockdown neurons. We also found that the efficiency of synaptic transmission was reduced in the hippocampus of Shp2 cKO mice. In addition, post-tetanic potentiation and paired pulse facilitation were attenuated and enhanced, respectively, in the hippocampal slice prepared from Shp2 cKO mice. They also showed temporary impaired memory formation in Morris water maze. These data suggest that Shp2 participates in regulation of activation of MAPK and synaptic plasticity in post-mitotic forebrain neurons, and thus contributes to regulation of locomotor activity and memory formation.