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Mammalian target of rapamycin (mTOR) signaling pathway
mTOR is a conserved serine/threonine protein kinase that is a member of the phosphati- dylinositol 3-kinase related kinase (PIKK) family and functions as catalytic subunit of two distinct multi-protein complexes called mTORC1 and mTORC2. mTOR acts as molecular sensor of nutrients, cellular energy status, hormones, growth factors, cytokines and a large variety of environmental cues that are integrated and transmitted as signals to downstream targets to regulate cell growth and homeostasis 36, 66. Neural activity-de- pendent regulation represents a characteristic feature of mTOR activation in the cen- tral nervous system (CNS) 67. Accordingly, in neurons mTOR function has been shown to be influenced by the activities of neurotransmitter receptors, including N-methyl-D- aspartate receptors (NMDA; ionotropic glutamate receptor, GluN), α-amino-3-hydroxy- 5-methyl-4-isoxazolepropionic acid receptors (AMPA; ionotropic glutamate receptor, GluA) and G-protein coupled receptors, such as μ-opioid, dopaminergic, metabotropic glutamate and cannabinoid and serotonin receptors (for reviews see 67-70). Thus, it is not really surprising that mTOR pathway exerts a key role during development of the cerebral cortex, regulating cell proliferation, growth, autophagy, apoptosis, and migra- tion, and that its aberrant signaling may disrupt corticogenesis and interfere with proper myelination in the CNS 69, 71, 72. Over the past decade several studies provided strong evi- dence of the critical role of the mTOR pathway during neural development, particularly in the maintenance of neural stem cell (NSC) undifferentiated state, in axon and dendrite development, in neuron and astrocyte differentiation, as well as in oligodendrocyte lin- eage development 73, 74.
Dysregulation of the mTOR signaling pathway can lead to a variety of neuro- logical disorders including both neurodevelopmental and neurodegenerative diseases, characterized by a clinical phenotype including autism, intellectual disability and epilepsy 62, 66, 75-78. mTOR dysregulation has been implicated in a large spectrum of genetic and acquired forms of epileptogenesis, including TSC and focal cortical dysplasia (FCD) 61-65.
Tuberous sclerosis complex and mTOR
mTORC1, the downstream target of TSC1 and TSC2, inhibits a large variety of cell signal- ing pathways, controlling many cellular processes including protein synthesis, lipogene- sis, ribosomal and mitochondrial biogenesis and autophagy. Rapamycin and its derivates, such as everolimus and sirolimus, act as specific mTORC1 inhibitors (Fig 2; 66, 76, 79, 80). Loss-of-function mutations in either TSC1 or TSC2 lead to constitutive mTOR activation, resulting in an abnormal development of the cerebral cortex with alterations in cortical lamination, cell size and axon and dendrite growth and multiple focal brain structural abnormalities 39. These regions of abnormal development represent the neuropathologi- cal substrates of the complex neurological manifestations of TSC, including neurobehav- ioral dysfunctions and severe epilepsy 23, 81.
FCD, which represents another frequent substrate in pediatric epilepsy surgery patients (see Fig 3 for a schematic overview of the disturbed cortical layers in FCD) 20, 82, 83, is also characterized by an overactivation of the mTOR pathway and can thus also be classified under the term “mTORopathies” (mTOR pathway-related malformations), which has been introduced to define a spectrum of MCDs characterized by altered cor- tical architecture, abnormal neuronal and glial morphology and intractable seizures as