title: 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.
authors.affiliation: Laboratory of Biosignal Sciences, Institute for Molecular and Cellular Regulation, Gunma University, Gunma, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Kusakari
authors.affiliation: Department of Pharmacology, Nippon Medical School, Tokyo, Japan.
authors.forename: Fumihito
authors.initials: F
authors.lastname: Saitow
authors.affiliation: Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Ago
authors.affiliation: Department of Molecular and Cellular Neurobiology, Gunma University Graduate School of Medicine, Gunma, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Shibasaki
authors.affiliation: Department of Laboratory Sciences, Gunma University Graduate School of Health Sciences, Gunma, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Sato-Hashimoto
authors.affiliation: Department of Neurophysiology, Gunma University Graduate School of Medicine, Gunma, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Matsuzaki
authors.affiliation: Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Takenori
authors.initials: T
authors.lastname: Kotani
authors.affiliation: Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Yoji
authors.initials: Y
authors.lastname: Murata
authors.affiliation: Department of Neurophysiology, Gunma University Graduate School of Medicine, Gunma, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Hirai
authors.affiliation: Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Matsuda
authors.affiliation: Department of Pharmacology, Nippon Medical School, Tokyo, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: 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.
authors.forename: Takashi
authors.initials: T
authors.lastname: Matozaki
authors.affiliation: 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.
authors.forename: Hiroshi
authors.identifier: http://orcid.org/0000-0002-2534-5449
authors.initials: H
authors.lastname: Ohnishi
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D017781:Genes, Immediate-Early; D008124:Locomotion; D020935:MAP Kinase Signaling System; D008297:Male; D008568:Memory; D051379:Mice / Q000235:genetics / Q000502:physiology*; D018345:Mice, Knockout; D009473:Neuronal Plasticity; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D016548:Prosencephalon / Q000166:cytology* / Q000502:physiology; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D034741:RNA, Small Interfering; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11