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Mol Cell Biol. 2015 May;35(9):1557-72. doi: 10.1128/MCB.01339-14. Epub 2015 Feb 23.

Shp2 in forebrain neurons regulates synaptic plasticity, locomotion, and memory formation in mice.

Author information

1
Laboratory of Biosignal Sciences, Institute for Molecular and Cellular Regulation, Gunma University, Gunma, Japan.
2
Department of Pharmacology, Nippon Medical School, Tokyo, Japan.
3
Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
4
Department of Molecular and Cellular Neurobiology, Gunma University Graduate School of Medicine, Gunma, Japan.
5
Department of Laboratory Sciences, Gunma University Graduate School of Health Sciences, Gunma, Japan.
6
Department of Neurophysiology, Gunma University Graduate School of Medicine, Gunma, Japan.
7
Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Japan.
8
Laboratory of Biosignal Sciences, Institute for Molecular and Cellular Regulation, Gunma University, Gunma, Japan Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Japan matozaki@med.kobe-u.ac.jp ohnishih@gunma-u.ac.jp.
9
Laboratory of Biosignal Sciences, Institute for Molecular and Cellular Regulation, Gunma University, Gunma, Japan Department of Laboratory Sciences, Gunma University Graduate School of Health Sciences, Gunma, Japan matozaki@med.kobe-u.ac.jp ohnishih@gunma-u.ac.jp.

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.

PMID:
25713104
PMCID:
PMC4387209
DOI:
10.1128/MCB.01339-14
[Indexed for MEDLINE]
Free PMC Article

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