Basic research on cognitive impairments in Noonan Syndrome: the NMDA-D1 receptor complex as a novel pharmacological target for the management of these disabilities

Noonan Syndrome is a rare and multisystemic genetic disorder, linked to mutations in genes coding for proteins controlling the Ras/MAPK/Erk cascade, such as Shp-2, that clinically includes a broad range of manifestations spanning from growth abnormalities, cardiovascular diseases, and elevated susceptibility to tumors. Moreover, 30-50% of NS patients suffer from cognitive disabilities for which there are no cures. The major signal underlying the pathogenesis of several Noonan Syndrome-related defects, including cognitive disabilities, is an enhanced activation of the intracellular Erk1/2 pathway. In this study, we hypothesize that Erk1/2 neuronal activation is mediated by a novel heteromeric complex composed of the NMDA receptors and dopamine D1 receptors (NMDA-D1R complex) that involve the tyrosine phosphatase Shp-2. Thus, the NMDA-D1R complex may represent a novel pharmacological target for compounds acting through this molecular unit, able to normalize abnormal Erk1/2 and useful for rescuing from cognitive impairment in NS. This study will be conducted in mouse neurons derived from an animal model of Noonan Syndrome with cognitive deficits and in human glutamatergic neurons derived from induced pluripotent stem cell lines obtained from Noonan Syndrome patients with cognitive disabilities. Moreover, the possibility of affecting cognitive deficits by the pharmacological modulation of the NMDA-D1R complex will be validated by returning to the mouse model with molecular and behavioral studies.