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Nat Neurosci. 2014 Dec;17(12):1736-43. doi: 10.1038/nn.3863. Epub 2014 Nov 10.

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

Author information

1
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. [2] Department of Life Science, Chung-Ang University, Seoul, Korea.
2
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.
3
Department of Medicine and Microbiology, College of Medicine, Signaling Disorder Research Center, Chungbuk National University, Cheongju, Korea.
4
Department of Life Science, Chung-Ang University, Seoul, Korea.
5
School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, Korea.
6
Department of Neurology, University of Wisconsin-Madison, Madison, Wisconsin, USA.
7
Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.

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 PTPN11(D61G) 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 Ptpn11(D61G/+) 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.

PMID:
25383899
PMCID:
PMC4716736
DOI:
10.1038/nn.3863
[Indexed for MEDLINE]
Free PMC Article

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