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Mechanism for the learning deficit in mouse
models of Noonan syndrome
Yong Seok Lee
University of California, Los Angeles, Postdoctoral fellow in
Department of Neurobiology
11:00-12:00, July 05, Tuesday, 2011
Room 103, Building 1, DGIST
Noonan syndrome (NS) is a common genetic disorder with an incidence of 1 in
~2,500. One third of NS patients show cognitive deficits, including learning
disabilities and mental retardation. Mutations in the PTPN11 gene, which encodes the
non-receptor protein tyrosine phosphatase SHP-2, account for ~50% of NS cases.
Although NS-associated SHP-2 mutants have been shown to up-regulate Ras-ERK
signaling, little is known about the role of SHP-2 in synaptic plasticity and learning &
memory. Here, we report that two mutant mouse lines expressing NS-associated gainof-function SHP-2 mutants show deficits in a hippocampus-dependent learning task,
the Morris water maze. Accordingly, SHP-2 mutants with behavioral deficits also
show decreased long-term potentiation (LTP) in the hippocampal Schaffer Collateral
pathway. To determine whether abnormal SHP-2 signaling in the adult brain
contributes to these deficits, we used viral vectors (rAAV-SHP-2D61G) to
overexpress a NS-associated mutant SHP-2 D61G in the dorsal hippocampus of adult
mice. SHP-2D61G overexpression resulted in hyperactivation of ERK signaling,
deficits in hippocampal CA1 LTP and spatial learning abnormalities. Importantly, a
pharmacological manipulation that reduces ERK activation reversed the LTP and
learning deficits in rAAV-SHP-2D61G mice, suggesting that increased ERK signaling
may underlie the learning disabilities associated with NS. Our results implicate SHP2 function in CA1-dependent LTP and learning & memory, they suggest that
increases in ERK signaling and LTP deficits are responsible for the learning deficits
in NS, and that pharmacological agents that dampen ERK signaling may be used in
treating the learning & memory deficits in NS.
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Person in charge : Jeong Min Lee
Contact: [email protected], 053)785-6101