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Increased Src Family Kinase Activity Disrupts Excitatory Synaptic Transmission and Impairs Remote Fear Memory in Forebrain Shp2-Deficient Mice

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Abstract

Src homolog domain-containing phosphatase 2 (Shp2) signals a variety of cellular and physiological functions including learning and memory. Dysregulation of ERK signaling is known to be responsible for the cognitive deficits associated with gain-of-function mutated Shp2 mimicking Noonan syndrome. However, here, we report that CaMKIIα-cre induced knockout (CaSKO) of Shp2 in hippocampal pyramidal neurons resulted in increased Src activity, upregulated phosphorylation of N-methyl-D-aspartate receptors (NMDARs) at Y1325 of GluN2A and at Y1472 of GluN2B, disrupted the balance of synaptic transmission, and impaired long-term potentiation and remote contextual fear memory. Administration of PP2, a specific Src family kinase inhibitor, reversed the tyrosine phosphorylation of NMDARs, restored basal synaptic transmission, and rescued the contextual fear memory deficit in CaSKO mice without altering the phospho-ERK level. Taken together, our results reveal a novel role of Shp2 in NMDAR-dependent synaptic function and fear memory via the Src signaling pathway rather than the ERK pathway, and suggest a complicated mechanism for Shp2-associated cognitive deficits.

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Acknowledgments

We thank Gensheng Feng (University of California San Diego) for the Shp2 flox/flox mice and Zhiqi Xiong (Institute of Neuroscience, Chinese Academy of Sciences) for the CaMKII-Cre mice. We thank Dr. J Julius Zhu (University of Virginia) and Dr. I.C. Bruce for critical reading of this manuscript.

Author Contributions

W.Y., X.Y.Y., and J.H.L. conceived and designed the experiments and wrote the manuscript; X.Y.Y., W.Y., W.C., and S.L. performed behavioral experiments; X.Y.Y., Q.Y., and W.C. performed electrophysiology experiments; B.Z., W.L., and L.P. performed biochemical experiments; X.Y.Y. and W.Y.Y. performed immunocytochemical experiments; Y.H.K. provided Shp2 FloxP/FloxP mice; X.Y.Y., B.Z., and S.L. analyzed data; and X.Y.Y., S.L., W.Y.Y., and W.C. did the genotyping of mice. W.Y. and J.H.L. supervised the studies in Zhejiang University; S.T.L. supervised the studies in Shanghai Jiaotong University.

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Authors and Affiliations

  1. Department of Neurobiology, Key Laboratory of Medical Neurobiology (Ministry of Health of China), Collaborative Innovation Center for Brain Science, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China

    Xunyi Yan, Bin Zhang, Wen Lu, Lin Peng, Wei Cao, Shen Lin, Wenyue Yu, Xiaoming Li, Wei Yang & Jianhong Luo

  2. Department of Pathology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China

    Yuehai Ke

  3. BIO-X Institute, Shanghai Jiaotong University, Shanghai, 200240, China

    Qian Yang & Shengtian Li

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Correspondence to Wei Yang or Jianhong Luo.

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Funding

This work was supported by grants from the Natural Science Foundation of China (81671162, 91232303, and 81221003 to J.H.L. and 30900418 to W.Y.), the National Basic Research Program of China (grant numbers 2010CB912002 and 2014CB910300 to J.H.L., 2013CB910204 to W.Y., and 2010CB912004 to Y.H.K.), and Fundamental Research Funds for the Central Universities of China.

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The authors declare no competing financial interest.

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Xunyi Yan and Bin Zhang contributed equally to this work.

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Yan, X., Zhang, B., Lu, W. et al. Increased Src Family Kinase Activity Disrupts Excitatory Synaptic Transmission and Impairs Remote Fear Memory in Forebrain Shp2-Deficient Mice. Mol Neurobiol 54, 7235–7250 (2017). https://doi.org/10.1007/s12035-016-0222-7

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