The role of mTOR in the cortical development has become clear to such a point that the pathologies caused by the various mutations in this pathway are known as "mTORopathies", being tuberous scleroris complex (TSC) and focal cortical dysplasia (FCD) the prototypes. TSC is a multi-system disorder (1/6000) caused by mutations in the Tsc1 or Tsc2 genes, while FCD shares many histopathological and clinical features with TSC such as autism, neuropsychiatric disorders and drug-resistant epileptic seizures that often oblige the patients to complex surgical interventions. Up to now, drugs that inhibit the mTOR pathway (the "rapalogs") have yielded sub-optimal results. Indeed, the amelioration of the neurological symptoms is flanked by unpleasant side-effects caused by the systemic drawbacks of mTOR blockade. Therefore, there is the need of a strategy which can target mechanisms located downstream this pathway. In these regards, a potential candidate is the neurotransmission: the excitation/inhibition balance is altered in various neurodevelopmental pathologies including the mTORopathies as TSC and FCD.
Our objective is to analyze the TSC and FCD's neurotransmission in samples with different mutations of mTOR pathway to outline an electrophysiological profile of each genetic mutation. This approach will involve next-generation sequencing, relative molecular validation on surgical TSC and FCD tissues, and electrophysiology in Xenopus oocytes transplanted with cortical membranes from the same tissues. The patch-clamp recordings on cortical slices from patients will complete the picture. Further experiments based on the results of transcriptome and molecular analysis, will test drugs able to modulate the altered neurotransmission in mTORopathies. The expected output is to gather deeper knowledge of the physiopathology of neurotransmission linked to mTOR alterations and to pave the road for future studies in order to bring this "synapse-targeted" approach to clinical practice.
