Hippocampal synaptic modulation by the phosphotyrosine adapter protein ShcC/N-Shc via interaction with the NMDA receptor.
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.
Miyamoto
Yoshiaki
Y
Department of Molecular Genetics, National Institute for Longevity Sciences, Oobu 474-8522, Japan.
Chen
Ling
L
Sato
Masahiro
M
Sokabe
Masahiro
M
Nabeshima
Toshitaka
T
Pawson
Tony
T
Sakai
Ryuichi
R
Mori
Nozomu
N
D020816:Amino Acid Motifs; D000818:Animals; D001362:Avoidance Learning / Q000502:physiology*; D003214:Conditioning, Classical; D005239:Fear / Q000502:physiology*; D006624:Hippocampus / Q000502:physiology*; D017774:Long-Term Potentiation / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology; D018782:Maze Learning / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D009473:Neuronal Plasticity; D009479:Neuropeptides / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000737:chemistry; D011499:Protein Processing, Post-Translational; D020813:Receptor, trkB / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D021641:Recognition, Psychology / Q000502:physiology*; D055765:Shc Signaling Adaptor Proteins; D000071427:Src Homology 2 Domain-Containing, Transforming Protein 3; D013569:Synapses / Q000502:physiology*
C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D016194:Receptors, N-Methyl-D-Aspartate; D055765:Shc Signaling Adaptor Proteins; C485682:Shc3 protein, mouse; D000071427:Src Homology 2 Domain-Containing, Transforming Protein 3; D019000:Phosphotyrosine; D020813:Receptor, trkB
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