The mTOR (mammalian target of rapamycin) is a ubiquitous intracellular pathway. Its name refers to rapamycin, a pharmacological agent that inhibits this pathway. mTOR is a protein kinase present in the cell in two complexes, mTORC1 and mTORC2, which differ in composition and function. The signaling pathway integrates various extra- and intra-cellular signals such as nutrients, cellular energy level, hormones, cytokines and the activities of neurotransmitter receptors. The mTOR pathway controls major cellular functions, including protein synthesis, cell growth and proliferation, and cellular polarization [1]. The mTOR pathway also has a critical role during brain development, including axon and dendrite development, neuron and astrocytes differentiation, and synaptic plasticity [2].

Inhibitors of the growth factor and amino acid-mediated mTORC1 signaling pathways are key for regulating metabolic homeostasis. This review will focus on these two branches: (i) The growth factor sensing machinery, which includes the tuberous sclerosis complex (TSC) protein complex, encoded by TSC1 (hamartin), TSC2 (tuberin), and TBC1D7 genes; (ii) the amino acid sensing machinery consisting of GATOR1, a protein complex composed of DEP domain-containing protein 5 (DEPDC5), NPR2 like (NPRL2), and NPR3 like (NPRL3) [3] (Fig. 1).

Constitutive activation of the pathway due to germline mutations in TSC1/TSC2 or the GATOR1-coding gene complex cause, respectively tuberous sclerosis complex (TSC) and familial focal epilepsies. Recently, somatic mutations in several mTOR pathway genes have emerged as a frequent cause of focal cortical malformations from hemimegalencephaly (HME) to type II focal cortical dysplasia (FCD II), leading to the concept of “mTORopathies” (mTOR pathway-related malformations) [4], [5] (Fig. 1). Altogether these findings also led to the hypothesis that mTOR inhibitors could be used as antiseizure medication. The objective of this review, based on the symposium on this topic given at the 2022 epilepsy meeting of the French chapter of the ILAE, is to review the current reports on the use of pharmacological treatment targeting the mTOR pathway for epilepsy.