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

Noonan syndrome (NS) is an autosomal dominant genetic disease that is co-morbid with cognitive deficits in a subset of patients. Using mouse models of NS, a study now shows that the synaptic plasticity and memory deficits in mouse models of NS are due primarily to the dysfunction in the MEK-Erk kinase pathways, and pharmacological intervention that alters MEK-Ras function can alleviate physiological and behavioral deficits in the mouse models of NS. 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.