The mammalian target of rapamycin (mTOR) signaling pathway regulates cell growth, differentiation, proliferation, and metabolism.
Loss-of-function mutations in upstream regulators of mTOR have been highly associated with dysplasias, epilepsy, and neurodevelopmental
disorders. These include tuberous sclerosis, which is due to mutations in TSC1 or TSC2 genes; mutations in phosphatase and
tensin homolog (PTEN) as in Cowden syndrome, polyhydramnios, megalencephaly, symptomatic epilepsy syndrome (PMSE) due to mutations
in the STE20-related kinase adaptor alpha (STRADalpha); and neurofibromatosis type 1 attributed to neurofibromin 1 mutations.
Inhibition of the mTOR pathway with rapamycin may prevent epilepsy and improve the underlying pathology in mouse models with
disrupted mTOR signaling, due to PTEN or TSC mutations. However the timing and duration of its administration appear critical
in defining the seizure and pathology-related outcomes. Rapamycin application in human cortical slices from patients with
cortical dysplasias reduces the 4-aminopyridine-induced oscillations. In the multiple-hit model of infantile spasms, pulse
high-dose rapamycin administration can reduce the cortical overactivation of the mTOR pathway, suppresses spasms, and has
disease-modifying effects by partially improving cognitive deficits. In post-status epilepticus models of temporal lobe epilepsy,
rapamycin may ameliorate the development of epilepsy-related pathology and reduce the expression of spontaneous seizures,
but its effects depend on the timing and duration of administration, and possibly the model used. The observed recurrence
of seizures and epilepsy-related pathology after rapamycin discontinuation suggests the need for continuous administration
to maintain the benefit. However, the use of pulse administration protocols may be useful in certain age-specific epilepsy
syndromes, like infantile spasms, whereas repetitive-pulse rapamycin protocols may suffice to sustain a long-term benefit
in genetic disorders of the mTOR pathway. In summary, mTOR dysregulation has been implicated in several genetic and acquired
forms of epileptogenesis. The use of mTOR inhibitors can reverse some of these epileptogenic processes, although their effects
depend upon the timing and dose of administration as well as the model used.