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Mechanism and treatment for learning and memory deficits in mouse models of Noonan syndrome

Nature Neuroscience volume 17, pages 17361743 (2014) | Download Citation

Abstract

In Noonan syndrome (NS) 30–50% of subjects show cognitive deficits of unknown etiology and with no known treatment. Here, we report that knock-in mice expressing either of two NS-associated mutations in Ptpn11, which encodes the nonreceptor protein tyrosine phosphatase Shp2, show hippocampal-dependent impairments in spatial learning and deficits in hippocampal long-term potentiation (LTP). In addition, viral overexpression of an NS-associated allele PTPN11D61G in adult mouse hippocampus results in increased baseline excitatory synaptic function and deficits in LTP and spatial learning, which can be reversed by a mitogen-activated protein kinase kinase (MEK) inhibitor. Furthermore, brief treatment with lovastatin reduces activation of the GTPase Ras–extracellular signal-related kinase (Erk) pathway in the brain and normalizes deficits in LTP and learning in adult Ptpn11D61G/+ mice. Our results demonstrate that increased basal Erk activity and corresponding baseline increases in excitatory synaptic function are responsible for the LTP impairments and, consequently, the learning deficits in mouse models of NS. These data also suggest that lovastatin or MEK inhibitors may be useful for treating the cognitive deficits in NS.

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Acknowledgements

The authors would like to thank I. Mody, T. O'Dell, P. Golshani and members of A.J.S.'s lab for their comments on the manuscript and for valuable discussions; R. Jones and Y. Zhou for helping with electrophysiological analysis; D.Y. Cai for statistical advice; and A. Amin, H. Shan and R. Knier for technical support. This work was supported by MH084315 to A.J.S., NRF-2013R1A1A1006766 and NRF-2013R1A3A1072570 to Y.-S.L, R37 CA49132 to B.G.N and MEST-2012-0005751 to H.K.K. B.G.N. is also a Canada Research Chair, Tier 1, and work in his lab is partially supported by the Ontario Ministry of Health and Long Term Care and the Princess Margaret Cancer Foundation.

Author information

Author notes

    • Dan Ehninger
    •  & J Balaji

    Present addresses: DZNE, German Center for Neurodegenerative Diseases, Bonn, Germany (D.E.) and Center for Neuroscience, Indian Institute of Science, Bangalore, India (J.B.).

Affiliations

  1. Integrative Center for Learning and Memory, Departments of Neurobiology, Psychiatry and Biobehavioral Sciences, Psychology and Brain Research Institute, University of California Los Angeles, Los Angeles, California, USA.

    • Yong-Seok Lee
    • , Dan Ehninger
    • , Miou Zhou
    • , Ying Cai
    • , J Balaji
    • , Yoshitake Sano
    • , Christine I Nam
    •  & Alcino J Silva
  2. Department of Life Science, Chung-Ang University, Seoul, Korea.

    • Yong-Seok Lee
    • , Minkyung Kang
    •  & Hyun-Hee Ryu
  3. Department of Medicine and Microbiology, College of Medicine, Signaling Disorder Research Center, Chungbuk National University, Cheongju, Korea.

    • Jun-Young Oh
    •  & Hyong Kyu Kim
  4. School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, Korea.

    • Chuljung Kwak
    •  & Bong-Kiun Kaang
  5. Department of Neurology, University of Wisconsin-Madison, Madison, Wisconsin, USA.

    • Delana Butz
    •  & Corinna Burger
  6. Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.

    • Toshiyuki Araki
    •  & Benjamin G Neel

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Contributions

Y.-S.L., D.E. and A.J.S. conceptualized the research, designed the experiments and wrote the manuscript; Y.-S.L., D.E., M.Z., M.K., H.-H.R., C.K. C.I.N. and Y.C. performed behavioral experiments; Y.-S.L performed whole-cell patch clamp recordings; Y.-S.L., M.Z. and Y.S. performed LTP recording and biochemical analyses; J.-Y.O. and H.K.K. performed immunocytochemistry and biotinylation experiments; T.A. and B.G.N. provided Ptpn11D61G/+ and Ptpn11N308D/+ founders, discussed the results and edited the manuscript; D.B. and C.B. packaged viral vectors; Y. -S.L., D.E., M.Z., J.B., H.K.K. and B.-K.K. analyzed the data and discussed the results.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Yong-Seok Lee or Alcino J Silva.

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DOI

https://doi.org/10.1038/nn.3863

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