FIGURE 3. Role of mTOR pathway in cortical dysplasias and epileptogenesis.

The mTOR pathway can become hyperactive (thick lines) by mutations of genes encoding upstream regulators (TSC1, TSC2, STRADA, PTEN or NF-1), components of the pathways that converge on TCS1/2, such as RAF, AKT, PI3K and also of mTOR (highlighted in red). The recent discovery of HPV16 E6 in FCD type IIa and IIb along with other DNA viruses suggest that an infectious etiology can contribute to the pathogenesis of this condition. Together, activated mTOR pathway results in abnormally increased cell growth and proliferation that could account for the anatomical lesions encountered in cortical dysplasias. In addition, enhanced mTOR signaling can modify the expression of neurotransmitter receptors and ion channels, which can change membrane properties and synaptic organization leading to neuronal hyperexcitability. Both morphological and functional alterations at the cellular and circuit levels may lead to epilepsy, focal deficits and cognitive dysfunction in patients with cortical dysplasias.^{15; 30; 31; 35; 38; 43; 54; 59; 67}