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

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

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

Sleep orchestrates indices of local plasticity and global network stability in the human cortex.

Animals and humans spend on average one third of their lives in sleep, but its functions remain to be specified. Distinct lines of research propose that sleep promotes local strengthening of information-bearing synapses (plasticity) and global downscaling of synaptic strength (stability) in neural networks-prerequisites for adaptive behavior in a changing environment. However, the potential orchestration of these processes, particularly in humans, needs to be further characterized. Here, we use electrophysiological, behavioral, and molecular indices to noninvasively study cortical plasticity and network stability in humans. We observe indices of local strengthening of prior induced long-term potentiation-like plasticity (paired associative stimulation induced change in motor-evoked potential) and global network stabilization (homeostatic regulation of wake EEG theta activity) after brief periods of nonrapid eye movement sleep compared with wakefulness. The interplay of local sleep slow oscillations and spindle activity, previously related to synaptic refinements during sleep, is identified as a potential mechanism. Our findings are consistent with the notion that sleep-specific brain activity patterns reduce the plasticity-stability dilemma by orchestrating local plasticity and global stability of neural assemblies in the human cortex. Future studies are needed to further decipher the neural mechanisms underlying our indirect observations