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The Journal of Neuroscience, February 16, 2005, 25(7):1826-1835; doi:10.1523/JNEUROSCI.3030-04.2005

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Behavioral/Systems/Cognitive
Hippocampal Synaptic Modulation by the Phosphotyrosine Adapter Protein ShcC/N-Shc via Interaction with the NMDA Receptor

Yoshiaki Miyamoto,¹ Ling Chen,² Masahiro Sato,¹ Masahiro Sokabe,^2,3 Toshitaka Nabeshima,⁴ Tony Pawson,⁵ Ryuichi Sakai,⁶ and Nozomu Mori^1,7

¹Department of Molecular Genetics, National Institute for Longevity Sciences, Oobu 474-8522, Japan, ²Cell Mechanosensing Project, International Cooperative Research Project-Japan Science and Technology Agency, and Departments of ³Physiology and ⁴Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan, ⁵Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada, ⁶Growth Factor Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan, and ⁷Department of Anatomy and Neurobiology, Nagasaki University School of Medicine, Nagasaki 852-8523, Japan

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.

Key words: ShcC/N-Shc; phosphotyrosine adapter protein; learning and memory; long-term potentiation; hippocampus; NMDA receptor

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Received March 3, 2004; revised December 30, 2004; accepted January 3, 2005.

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