Hippocampal synaptic modulation by the phosphotyrosine adapter protein ShcC/N-Shc via interaction with the NMDA receptor

Yoshiaki Miyamoto, Ling Chen, Masahiro Sato, Masahiro Sokabe, Toshitaka Nabeshima, Tony Pawson, Ryuichi Sakai, Nozomu Mori

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

N-Shc (neural Shc) (also ShcC), an adapter protein possessing two phosphotyrosine binding motifs [PTB (phosphotyrosine binding) and SH2 (Src homology 2) domains], is predominantly expressed in mature neurons of the CNS and transmits neurotrophin signals from the TrkB receptor to the Ras/mitogen-activated protein kinase (MAPK) pathway, leading to cellular growth, differentiation, or survival. Here, we demonstrate a novel role of ShcC, the modulation of NMDA receptor function in the hippocampus, using ShcC gene-deficient mice. In behavioral analyses such as the Morris water maze, contextual fear conditioning, and novel object recognition tasks, ShcC mutant mice exhibited superior ability in hippocampus-dependent spatial and nonspatial learning and memory. Consistent with this finding, electrophysiological analyses revealed that hippocampal long-term potentiation in ShcC mutant mice was significantly enhanced, with no alteration of presynaptic function, and the effect of an NMDA receptor antagonist on its expression in the mutant mice was notably attenuated. The tyrosine phosphorylation of NMDA receptor subunits NR2A and NR2B was also increased, suggesting that ShcC mutant mice have enhanced NMDA receptor function in the hippocampus. These results indicate that ShcC not only mediates TrkB-Ras/MAPK signaling but also is involved in the regulation of NMDA receptor function in the hippocampus via interaction with phosphotyrosine residues on the receptor subunits and serves as a modulator of hippocampal synaptic plasticity underlying learning and memory.

Original languageEnglish
Pages (from-to)1826-1835
Number of pages10
JournalJournal of Neuroscience
Volume25
Issue number7
DOIs
Publication statusPublished - 16-02-2005
Externally publishedYes

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Phosphotyrosine
N-Methyl-D-Aspartate Receptors
Hippocampus
Mitogen-Activated Protein Kinases
Proteins
trkB Receptor
Neuronal Plasticity
Aptitude
src Homology Domains
Long-Term Potentiation
Nerve Growth Factors
Fear
Tyrosine
Phosphorylation
Learning
Neurons
Water
Growth
Genes

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Cite this

Miyamoto, Yoshiaki ; Chen, Ling ; Sato, Masahiro ; Sokabe, Masahiro ; Nabeshima, Toshitaka ; Pawson, Tony ; Sakai, Ryuichi ; Mori, Nozomu. / Hippocampal synaptic modulation by the phosphotyrosine adapter protein ShcC/N-Shc via interaction with the NMDA receptor. In: Journal of Neuroscience. 2005 ; Vol. 25, No. 7. pp. 1826-1835.
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Hippocampal synaptic modulation by the phosphotyrosine adapter protein ShcC/N-Shc via interaction with the NMDA receptor. / Miyamoto, Yoshiaki; Chen, Ling; Sato, Masahiro; Sokabe, Masahiro; Nabeshima, Toshitaka; Pawson, Tony; Sakai, Ryuichi; Mori, Nozomu.

In: Journal of Neuroscience, Vol. 25, No. 7, 16.02.2005, p. 1826-1835.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Hippocampal synaptic modulation by the phosphotyrosine adapter protein ShcC/N-Shc via interaction with the NMDA receptor

AU - Miyamoto, Yoshiaki

AU - Chen, Ling

AU - Sato, Masahiro

AU - Sokabe, Masahiro

AU - Nabeshima, Toshitaka

AU - Pawson, Tony

AU - Sakai, Ryuichi

AU - Mori, Nozomu

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