Lovastatin improves impaired LTP-like plasticity in patients with Neurofibromatosis Type 1

Neurofibromatosis Type 1 (NF1) is one of the most common genetic disorders that causes learning disabilities. In NF1 loss of function mutations of neurofibromin causes RAS-pathway hyperactivity, leading to deficits in long-term potentiation (LTP), a basic mechanism of learning and memory in the mouse model. Recently, it was shown that inhibition of HMG-CoA reductase by Lovastatin reduces RAS-pathway hyperactivity and improves LTP in NF1 mice. The presented study shows that humans with NF1 have impaired LTP-like plasticity and that this impairment can be rescued by Lovastatin.

In 11 NF1-patients (28.0±9.2 y) and 11 healthy volunteers (24.9±3.5 y) the effect of paired associated stimulation (PAS) with 200 paired stimuli (rTMS0,25Hz and electrical wrist stimulation of the N. medianus, latency 25ms) on MEP amplitude (immediately (T0) and after 30 and 60 minutes (T30/60)). Furthermore the effect of a 4 day course of 200mg/day Lovastatin and placebo (double blind, randomized) was investigated. After PAS MEP amplitudes of healthy controls increased significantly (from 1.0±0.17 to 1.43±0.47 mV (T0), 1.60±0.71 mV (T30) and 1.71±0.51 mV (T60); p=0.002) in contrast to patients with NF1 where no increase was seen. Lovastatin significantly improved the PAS effect in these patients (from 0.84±0.47 mV to 1.44±0.52 mV (T0), 0.80±0.41 mV to 1.31±0.63 mV (T30), 0.92±0.33 mV to 1.39±0.73 mV (T60); p=0.012). In conclusion we demonstrated an impairment of LTP-like plasticity in NF1 patients which is improved by Lovastatin. This study underlines the role of RAS pathway in LTP-like plasticity in humans and may point towards new treatment strategies for cognitive deficits in NF1.