Impaired Synaptic Plasticity in Humans with RASopathies – An Update

Question: Synaptic plasticity forms of long-term potentiation (LTP) and long-term depression (LTD) is considered to be the neurophysiological correlate of learning and memory. Impairments are discussed to be one of the underlying pathophysiological mechanisms of developmental disorders. In so-called RASopathies, a group of disorders (e.g. neurofibromatosis type 1 (NF1)), neurocognitive impairments are frequent and are affected by components of the RAS pathway which leads to impairments in synaptic plasticity. Transcranial magnetic stimulation (TMS) provides a non-invasive method to investigate synaptic plasticity in humans. Here, we review studies using TMS to evaluate synaptic plasticity in patients with RASopathies.

Material and Method: A literature search in PubMed/Medline was performed in April 2019 with the following search criteria: “neurofibromatosis type 1” or “Noonan syndrome” or “Costello syndrome” or “Cardio-facio-cutaneous syndrome” or “Legius syndrome” or “Capillary Malformation–arteriovenous malformation syndrome”, and “RAS pathway” or “RASopathies”, and “transcranial magnetic stimulation” and “synaptic plasticity” and “humans”.

Results: We found four studies, investigating synaptic plasticity in patients with NF1, Noonan syndrome (NS) and Costello syndrome (CS). Patients with NF1 and NS demonstrated reduced cortical LTP-like synaptic plasticity. In a placebo controlled, randomized, double blind study, Lovastatin normalized impaired LTP-like plasticity and increased intracortical inhibition in patients with NF1. Patients with CS demonstrated in one experiment an increased LTP-like synaptic plasticity and in another experiment an impaired LTP-like synaptic plasticity, depending on the stimulation protocol used.

Discussion: Patients with NF1, NS and CS demonstrate impairments in LTP-like plasticity. These deficits may be restored by a downregulation of the hyperactive RAS pathway using Lovastatin in NF1. In patients with CS, paired associative stimulation (PAS) leads to an increased LTP-like plasticity while using intermittent theta burst stimulation (iTBS) showed an impaired synaptic plasticity LTP-like plasticity. This may point towards different pathophysiological mechanism of an impaired LTP-like plasticity in these patients. Deeper insights in the mechanisms of synaptic plasticity in RASopathies may help to develop new therapies of learning deficits in these patients.

Conclusion: The reported studies demonstrate that RASopathies (here, NF1, NS, and CS) share a common dysregulation in RAS pathway activity that results in deficits in LTP-like plasticity. In patients with NF1 and NS, a decreased LTP-like plasticity was found. Recently, it has been shown that patients with CS have an increased and impaired LTP-like plasticity, respectively, depending on the non-invasive brain stimulation protocol used.