MECHANISM AND TREATMENT FOR THE LEARNING AND MEMORY DEFICITS ASSOCIATED WITH MOUSE MODELS OF NOONAN SYNDROME

1 Departments of Neurobiology, Psychiatry and Biobehavioral Sciences, Psychology and Brain Research Institute, Integrative Center for Learning and Memory, University of California Los Angeles, Los Angeles, CA 90095, USA.
2 Campbell Family Cancer Research Institute, Ontario Cancer Institute, Princess Margaret Hospital, University Health Network, Toronto, ON, Canada M5G1L7.
3 Department of Neurology, University of Wisconsin-Madison, Madison, WI 53706, USA
“Current address: DZNE, German Center for Neurodegenerative Diseases, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany.
“Current address: Center for Neuroscience, Indian Institute of Science, Bangalore, 560012, India.

Noonan syndrome (NS) is an autosomal dominant genetic disorder with an incidence of ~l in 2,500 live births characterized by facial abnormalities, short stature, motor delay and cardiac defects. Importantly,  30% to 50% of NS patients show cognitive deficits. Mutations in the PTPN11 gene, which up-regulate  Ras-ERK signaling, account for ~50% of NS. We will report that heterozygous knock-in mice expressing  common NS-associated gain-of-function Ptpn11 mutations(Ptpn11^D61G/+ and Ptpn11N308D/+) show hippocampal-dependent spatial learning impairments caused by deficits in hippocampal long-term potentiation (LTP). First, we show that the learning and the LTP phenotypes associated with the more severe Ptpn11^D61G/+ mutation in mice are more profound than the LTP and learning phenotypes associated with milder Ptpn11N308D/+ mutation. Second, viral overexpression of the PTPN11^D61Ggene, specifically in adult CA fields of the hippocampus, results in increased basal ERK signaling, deficits in hippocampal CA1 LTP and consequently in spatial learning impairments, demonstrating that altered Ptpn11 function and associated LTP deficits specifically in adult CA fields are sufficient to cause spatial  learning deficits. Third, a MEK inhibitor (SL327), that targets the hyperactive ERK signaling pathway, can reverse the LTP and learning deficits caused by the PTPN11^D61Gmutation.

More importantly, we show that a brief treatment with an FDA approved drug (Iovastatin), which reduces Ras-ERK activation in the brain, rescues both the LTP and learning deficits in adult Ptpn11^D61G/+ mice, whereas the same lovastatin treatment does not affect wild type controls. Our results demonstrate that increased basal ERK signaling  and corresponding impairments in LTP are responsible for the learning deficits in mouse models of NS.

Interestingly, the cellular mechanism underlying the deficit in NS is different from that of Neurofibromatosis type I (NF1), a closely related disorder also characterized by learning and memory impairments. Previous studies in our laboratory shewed that the deficits in NFl were due to increased GABBA-mediated inhibition.