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.