Mechanisms underlying the cognitive deficits in animal models of rasopathies

Alcino J. Silva
Departments of Neurobiology, Psychiatry and Biobehavioral Sciences, Psychology and Brain Research Institute, UCLA Los Angeles, California 90095

Our laboratory has been studying the molecular and cellular mechanisms responsible for learning deficits in Rasopathies, a class of genetic disorders that alter Ras signaling mechanisms, and that result in a broad range of somatic, neurologic and psychiatric phenotypes. Although our work started with studies of neurofibromatosis type I (NF1), we have also studied several other rasophaties. For example, recently we uncovered molecular and cellular mechanisms responsible for the learning deficits associated with Noonan syndrome (NS), a genetic disorder with an incidence of 1 in ~2,500. As with NF1 patients, a significant percentage of NS patients show cognitive deficits, such as 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. Just as NF1, NS-associated SHP-2 mutants result in increases in Ras-ERK signaling, which is critically involved in learning and memory. However, unlike NF1, little is known about the role of SHP-2 in learning and memory and synaptic plasticity. Our laboratory recently found that similar to NF1 mouse mutants, mouse lines expressing two common NS-associated gain-of-function mutations show deficits in a hippocampus-dependent spatial learning task, as well as abnormalities in hippocampal long-term potentiation (LTP). To determine whether abnormal SHP-2 signaling in the adult brain is responsible for the behavioral deficits of these mutants, we overexpressed a NS-associated mutant SHP-2 D61G in the dorsal hippocampus of adult mice using viral vectors (rAAV). SHP-2D61G overexpression resulted in hyperactivation of ERK signaling, deficits of both hippocampal LTP and spatial learning. As with NF1, a pharmacological manipulation that reduces ERK activation reversed the LTP and learning deficits in rAAV transfected mice, indicating that increased ERK signaling underlies the deficits in LTP and learning associated with NS. These results may not only lead to the development of a potential treatment for learning deficits in NS, they are also giving us insights into how disruptions in Ras signaling could result in learning and memory impairments. These insights will be critical for the development of general treatments for rasophaties.

This work was supported by a grant from NIMH (MH084315) to AJS.