Journal
NATURE NEUROSCIENCE
Volume 17, Issue 12, Pages 1736-1743Publisher
NATURE PORTFOLIO
DOI: 10.1038/nn.3863
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Funding
- Ontario Ministry of Health and Long Term Care
- Princess Margaret Cancer Foundation
- [MH084315]
- [NRF-2013R1A1A1006766]
- [NRF-2013R1A3A1072570]
- [R37 CA49132]
- [MEST-2012-0005751]
- National Research Foundation of Korea [2007-0054930, 21A20131212408, 2012R1A3A1050385, 2013R1A1A1006766] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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 LIP 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.
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