Pathophysiology of neurodevelopmental mTOR pathway-associated epileptic conditions: Current status of biomedical...

Epilepsy is one of the most common and serious neurological disorders worldwide. It has no identifiable cause in approximately 50% of patients; in the other 50%, the condition may be due to a variety of etiologies and pathomechanisms. In this review, special focus is put on the prototypes of "mTORpathies": tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD) type IIb. We review recent research data on mTORpathies, with emphasis on cortical tubers and FCD-like lesions (neuronal migration lines (NML)). A major pathologic aspect in the network of drug-resistant epilepsy progression is the limited myelination of the white matter observed in these lesions. Recently, an association between the myelin pathology and dysregulation of the mTOR signaling pathway was observed by several studies. The lowered myelin content was shown to correlate not only with an increased mTOR expression but also with the relative duration of epilepsy. Another recently published finding in surgical tissue from patients with drug-resistant epilepsy and malformations of cortical development is inflammation. Accumulating evidence reports persistent and complex activation of inflammatory pathways in both cortical tubers and FCD lesions. Due to the fact that cortical tubers, as well as FCD lesions, are highly epileptogenic, a possible link between chronic seizure activity and the occurrence of an inflammatory response observed within the dysplastic cortex was postulated. Previously, alterations in the levels of classical complement C1q-C3 molecules in experimental and human epilepsy have been reported, suggesting that the classical complement pathway may be a novel candidate mechanism for the underlying epileptogenic circuit mechanism.
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