Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1

Abstract

Neurofibromatosis type I (NF1) is one of the most common single-gene disorders that causes learning deficits in humans. Mice carrying a heterozygous null mutation of the Nfl gene (Nfl(+/-) show important features of the learning deficits associated with NF1 (ref. 2). Although neurofibromin has several known properties and functions, including Ras GTPase-activating protein activity, adenylyl cyclase modulation and microtubule binding, it is unclear which of these are essential for learning in mice and humans. Here we show that the learning deficits of Nf1(+/-) mice can be rescued by genetic and pharmacological manipulations that decrease Ras function. We also show that the Nf1(+/-) mice have increased GABA (gamma-amino butyric acid)-mediated inhibition and specific deficits in long-term potentiation, both of which can be reversed by decreasing Ras function. Our results indicate that the learning deficits associated with NF1 may be caused by excessive Ras activity, which leads to impairments in long-term potentiation caused by increased GABA-mediated inhibition. Our findings have implications for the development of treatments for learning deficits associated with NF1.

A functional polymorphism in the succinate-semialdehyde dehydrogenase (aldehyde dehydrogenase 5 family, member A1) gene is associated with cognitive ability

“…27 Interestingly, the learning deficits in an animal model of neurofibromatosis type I have recently been attributed to deficits in LTP, resulting from increased GABA-mediated inhibition. 28 Moreover, as the LTP and learning deficits were reversed by GABA antagonist, the impairment is not likely to be attributable to neurotoxicity. This finding is again compatible with our observation of association between higher activity SSADH alleles (which are expected to reduce GABA) and higher general intelligence.…”

Neurofibromatosis 1

“…32 Studies in mice that are heterozygous for the Nf1 mutation, suggest that cognitive impairment in Nf1 is linked with excessive RAS activity and increased GABA inhibition in the hippocampus. 45 Furthermore, the learning problems and the GABA inhibition are reversed by a reduction in RAS, implying that farnesyl transferase inhibitor drugs might play a therapeutic role in cognitive impairment in Nf1. 45 The cholesterol lowering drug Lovastatin inhibits p21 RAS /mitogen activated protein kinase and a recent study demonstrated that the drug reverses learning and attention deficits in a mouse model of Nf1.…”

“…45 Furthermore, the learning problems and the GABA inhibition are reversed by a reduction in RAS, implying that farnesyl transferase inhibitor drugs might play a therapeutic role in cognitive impairment in Nf1. 45 The cholesterol lowering drug Lovastatin inhibits p21 RAS /mitogen activated protein kinase and a recent study demonstrated that the drug reverses learning and attention deficits in a mouse model of Nf1. 46 Currently, Lovostatin is being investigated as a potential treatment for cognitive impairment in children with Nf1.…”

Neuropsychological Functioning in Individuals with Noonan Syndrome: a Systematic Literature Review with Educational and Treatment Recommendations

“…In particular, great interest has developed with regard to interventions that might improve cognition, learning, and memory in the RASopathies (Shilyansky et al 2010b). Studies involving animal models of NF1 (e.g., Costa et al 2002) have led to the first clinical trials that target abnormal Ras signaling using statin drugs. Phase 1 trials indicate that these drugs can be safely prescribed in children with NF1, and there is some evidence that the drug lovastatin could affect specific cognitive outcomes (Acosta et al 2011).…”