The HMG-CoA reductase inhibitor lovastatin reverses the learning and attention deficits in a mouse model of neurofibromatosis type 1

Neurofibromatosis Type 1 (NF1) is a common neurological disorder caused by mutations in the gene encoding Neurofibromin, a p21Ras GTPase Activating Protein (GAP) [1]. Importantly, NF1 causes learning disabilities and attention deficits [2, 3]. A previous study showed that the learning and memory deficits of a mouse model of NF1 (nf1(+/-)) appear to be caused by excessive p21Ras activity leading to impairments in long-term potentiation (LTP) [4], a cellular mechanism of learning and memory [5-7]. Here, we identify lovastatin as a potent inhibitor of p21Ras/Mitogen Activated Protein Kinase (MAPK) activity [8, 9] in the brain. Lovastatin is a specific inhibitor of three-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, used commonly for the treatment of hypercholesterolemia [10]. We report that lovastatin decreased the enhanced brain p21 Ras-MAPK activity of the nf1(+/-) mice, rescued their LTP deficits, and reversed their spatial learning and attention impairments. Therefore, these results demonstrate that lovastatin may prove useful in the treatment of Neurofibromatosis Type 1.