Shp2 in Forebrain Neurons Regulates Synaptic Plasticity, Locomotion, and Memory Formation in Mice

Abstract

Shp2 (Src homology 2 domain-containing protein tyrosine phosphatase 2) regulates neural cell differentiation. It is also expressed in postmitotic neurons, however, and mutations of Shp2 are associated with clinical syndromes characterized by mental retardation. Here we show that conditional-knockout (cKO) mice lacking Shp2 specifically in postmitotic forebrain neurons manifest abnormal behavior, including hyperactivity. Novelty-induced expression of immediate-early genes and activation of extracellular-signal-regulated kinase (Erk) were attenuated in the cerebral cortex and hippocampus of Shp2 cKO mice, suggestive of reduced neuronal activity. In contrast, ablation of Shp2 enhanced high-K⁺-induced Erk activation in both cultured cortical neurons and synaptosomes, whereas it inhibited that induced by brain-derived growth factor in cultured neurons. Posttetanic potentiation and paired-pulse facilitation were attenuated and enhanced, respectively, in hippocampal slices from Shp2 cKO mice. The mutant mice also manifested transient impairment of memory formation in the Morris water maze. Our data suggest that Shp2 contributes to regulation of Erk activation and synaptic plasticity in postmitotic forebrain neurons and thereby controls locomotor activity and memory formation.

ACKNOWLEDGMENTS

We thank B. G. Neel and W. Yang for Shp2^flox/flox mice; E. Kramer and R. Klein for CRE-159 mice; T. Yamamoto and T. Nakazawa for antibodies to GluN2B; M. Takahashi for antibodies to VAMP2; S. C. Fujita for a monoclonal antibody to synaptophysin; H. Miyoshi for the lentiviral vector and packaging plasmids; M. Kobayashi, D. Kohno, T. Sasaki, and T. Kitamura for technical advice; and H. Kobayashi, E. Urano, Y. Kusakari, and Y. Hayashi for technical assistance.

This work was supported by a Grant-in-Aid for Scientific Research (C), a Grant-in-Aid for Young Scientists (B), and a grant-in-aid for Scientific Research on Innovative Areas (Brain Environment) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, as well as by grants from the Takeda Science Foundation, the Naito Foundation, the Japan Foundation for Neuroscience and Mental Health, and the Life Science Foundation of Japan. This work was carried out by the joint research program of the Institute for Molecular and Cellular Regulation, Gunma University (project 13017).