Abstract
RASopathies, characterized by germline mutations in genes encoding proteins of the RAS-ERK signaling pathway, show overlapping phenotypes, which manifest themselves with a varying severity of intellectual disability. However, it is unclear to what extent they share the same downstream pathophysiology that underlies the cognitive deficits. Costello syndrome (CS) is a rare RASopathy caused by activating mutations in the HRAS gene. Here we investigated the mechanisms underlying the cognitive deficits of HRasG12V/G12V mice. HRasG12V/G12V mice showed robust upregulation of ERK signaling, neuronal hypertrophy, increased brain volume, spatial learning deficits, and impaired mGluR-dependent long-term depression (LTD). In contrast, long-term potentiation (LTP), which is affected in other RASopathy mouse models was unaffected. Treatment with lovastatin, a HMG-CoA-Reductase inhibitor which has been shown to rescue the behavioral phenotypes of mouse models of NF1 and Noonan syndrome, was unable to restore ERK signaling and the cognitive deficits of HRasG12V/G12V mice. Administration of a potent mitogen-activated protein kinase (MEK) inhibitor rescued the ERK upregulation and the mGluR-LTD deficit of HRasG12V/G12V mice, but failed to rescue the cognitive deficits. Taken together, this study indicates that the fundamental molecular and cellular mechanisms underlying the cognitive aspects of different RASopathies are remarkably distinct, and may require disease specific treatments.
Highlights
In the last decade, several neurodevelopmental syndromes have been identified with germline mutations within key components of the highly conserved RAS-ERK signaling pathway[1,2,3]
An HRASG12V/G12V mouse model of Costello syndrome (CS) has been generated which displays several of the phenotypic abnormalities observed in CS patients, including facial dysmorphia and cognitive impairment[16, 17]
Mutant HRasG12V/G12V mice were born at the expected Mendelian ratio, were fertile, survived at rates comparable to those of their wild-type littermates, and displayed several of the phenotypic abnormalities observed in CS patients, including facial dysmorphia[16, 17]
Summary
Several neurodevelopmental syndromes have been identified with germline mutations within key components of the highly conserved RAS (rat sarcoma viral oncogene homolog)-ERK (extracellular signal regulated kinase) signaling pathway[1,2,3] These syndromes, including neurofibromatosis Type I (NF1), Noonan syndrome, LEOPARD syndrome, cardio-facio-cutaneous (CFC) syndrome, Costello syndrome, and Legius syndrome show significant phenotypic overlap and are referred to as RASopathies, the most common group of neurodevelopmental syndromes, affecting approximately 1 in 1,000 individuals[4]. Studies of several mouse models of RASophaties, including NF1, NS, and Legius syndrome, have demonstrated that dysregulation of the RAS-ERK pathway causes behavioral and learning deficits, altered synaptic plasticity, and structural brain abnormalities[8,9,10,11]. The cellular mechanism underlying these deficits as well as the ability to reverse them has not yet been studied
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