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  3. Medizin - Open Access LMU - Teil 20/22 Podcast
  4. Lovastatin improves impaired synaptic plasticity and phasic alertness in patients with neurofibromatosis type 1
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.

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