Beyond mTOR: Unraveling the Complex Pathophysiology and Signaling Pathways in Focal Cortical Dysplasia

Focal cortical dysplasia (FCD) is a common cause of drug-resistant epilepsy, characterized by abnormal cortical development and disrupted neuronal connectivity. The pathogenesis of FCD involves complex molecular mechanisms, among which the mTOR (mechanistic target of rapamycin) pathway has been extensively studied. Despite its well-established role in cellular growth and neurodevelopment, mTOR signaling does not fully explain the diverse clinical manifestations of FCD. This is evident in the resistance to mTOR inhibitors, which, although effective in some cases, fail to address the cognitive and behavioral deficits associated with the disorder. The limitations of mTOR-based therapies suggest that other signaling pathways and molecular factors may contribute to the pathophysiology of FCD. In this review, we innovatively conceptualize FCD as a spatiotemporally specific signaling disorder, with lesion formation resulting from the imbalance of multiple pathways interacting in distinct cell types. While mTOR is pivotal, its pathological effects are modulated and amplified by a network of signaling cascades, leading to subtype-specific pathway combinations in lesions. This mechanistic framework explains the clinical and histological heterogeneity of FCD and suggests that future studies should validate the causal relationships of specific pathways while exploring multi-target strategies beyond mTOR.