Lovastatin improves impaired synaptic plasticity and phasic alertness in patients with neurofibromatosis type 1

TY - JOUR

T1 - Lovastatin improves impaired synaptic plasticity and phasic alertness in patients with neurofibromatosis type 1

AU - Mainberger, Florian

AU - Jung, Nikolai H

AU - Zenker, Martin

AU - Wahlländer, Ute

AU - Freudenberg, Leonie

AU - Langer, Susanne

AU - Berweck, Steffen

AU - Winkler, Tobias

AU - Straube, Andreas

AU - Heinen, Florian

AU - Granström, Sofia

AU - Mautner, Victor-Felix

AU - Lidzba, Karen

AU - Mall, Volker

PY - 2013/1/1

Y1 - 2013/1/1

N2 - BACKGROUND: Neurofibromatosis type 1 (NF1) is one of the most common genetic disorders causing learning disabilities by mutations in the neurofibromin gene, an important inhibitor of the RAS pathway. In a mouse model of NF1, a loss of function mutation of the neurofibromin gene resulted in increased gamma aminobutyric acid (GABA)-mediated inhibition which led to decreased synaptic plasticity and deficits in attentional performance. Most importantly, these defictis were normalized by lovastatin. This placebo-controlled, double blind, randomized study aimed to investigate synaptic plasticity and cognition in humans with NF1 and tried to answer the question whether potential deficits may be rescued by lovastatin.METHODS: In NF1 patients (n = 11; 19-44 years) and healthy controls (HC; n = 11; 19-31 years) paired pulse transcranial magnetic stimulation (TMS) was used to study intracortical inhibition (paired pulse) and synaptic plasticity (paired associative stimulation). On behavioural level the Test of Attentional Performance (TAP) was used. To study the effect of 200 mg lovastatin for 4 days on all these parameters, a placebo-controlled, double blind, randomized trial was performed.RESULTS: In patients with NF1, lovastatin revealed significant decrease of intracortical inhibition, significant increase of synaptic plasticity as well as significant increase of phasic alertness. Compared to HC, patients with NF1 exposed increased intracortical inhibition, impaired synaptic plasticity and deficits in phasic alertness.CONCLUSIONS: This study demonstrates, for the first time, a link between a pathological RAS pathway activity, intracortical inhibition and impaired synaptic plasticity and its rescue by lovastatin in humans. Our findings revealed mechanisms of attention disorders in humans with NF1 and support the idea of a potential clinical benefit of lovastatin as a therapeutic option.

AB - BACKGROUND: Neurofibromatosis type 1 (NF1) is one of the most common genetic disorders causing learning disabilities by mutations in the neurofibromin gene, an important inhibitor of the RAS pathway. In a mouse model of NF1, a loss of function mutation of the neurofibromin gene resulted in increased gamma aminobutyric acid (GABA)-mediated inhibition which led to decreased synaptic plasticity and deficits in attentional performance. Most importantly, these defictis were normalized by lovastatin. This placebo-controlled, double blind, randomized study aimed to investigate synaptic plasticity and cognition in humans with NF1 and tried to answer the question whether potential deficits may be rescued by lovastatin.METHODS: In NF1 patients (n = 11; 19-44 years) and healthy controls (HC; n = 11; 19-31 years) paired pulse transcranial magnetic stimulation (TMS) was used to study intracortical inhibition (paired pulse) and synaptic plasticity (paired associative stimulation). On behavioural level the Test of Attentional Performance (TAP) was used. To study the effect of 200 mg lovastatin for 4 days on all these parameters, a placebo-controlled, double blind, randomized trial was performed.RESULTS: In patients with NF1, lovastatin revealed significant decrease of intracortical inhibition, significant increase of synaptic plasticity as well as significant increase of phasic alertness. Compared to HC, patients with NF1 exposed increased intracortical inhibition, impaired synaptic plasticity and deficits in phasic alertness.CONCLUSIONS: This study demonstrates, for the first time, a link between a pathological RAS pathway activity, intracortical inhibition and impaired synaptic plasticity and its rescue by lovastatin in humans. Our findings revealed mechanisms of attention disorders in humans with NF1 and support the idea of a potential clinical benefit of lovastatin as a therapeutic option.

KW - Adult

KW - Anticholesteremic Agents

KW - Attention

KW - Cerebral Cortex

KW - Cohort Studies

KW - Decision Making

KW - Double-Blind Method

KW - Evoked Potentials, Motor

KW - Female

KW - Humans

KW - Long-Term Potentiation

KW - Lovastatin

KW - Male

KW - Neural Inhibition

KW - Neurofibromatosis 1

KW - Time Factors

KW - Transcranial Magnetic Stimulation

KW - Young Adult

U2 - 10.1186/1471-2377-13-131

DO - 10.1186/1471-2377-13-131

M3 - SCORING: Journal article

C2 - 24088225

VL - 13

SP - 131

JO - BMC NEUROL

JF - BMC NEUROL

SN - 1471-2377

ER -