Evidence of mTOR pathway activation highlights similarities in the pathogenetic mechanisms underlying GG and focal cortical dysplasia, and suggests that mTOR inhibitors may be of utility in GG patients with persistent seizures after surgery.
The underlying mechanisms are not fully delineated; however, activation of mammalian target of rapamycin (mTOR) has been shown to be engaged in the pathogenesis of epilepsy, in which seizures are a regular occurrence.
We seek to understand the effect of mTOR dysregulation in a developing cortex with the propensity to generate seizures as well as the aftermath of the surrounding environment, including the white matter.
We used two experimental models of mTOR-dependent MCD consisting of conditional transgenic mice containing Tsc1<sup>null</sup> cells in the forebrain generating a global malformation associated with seizures and of wild-type mice containing a focal malformation in the somatosensory cortex generated by in utero electroporation (IUE) that does not lead to seizures.
Although Rheb and mTOR are implicated in the formation of cortical lesions, seizure activity, and defects in neuronal migration, the contribution of Rheb to changes in neuron size and dendrite morphology is not well established.
Recently, a double-blind phase III randomized clinical trial on patients with TSC related epilepsy, demonstrated that adjunctive treatment with mTOR inhibition is effective and safe in reducing focal drug resistant seizures.Expert commentary. mTOR signaling dysregulation represents a common pathogenic mechanism in a subset of malformations of cortical development, sharing histopathological and clinical features, including epilepsy, autism, and intellectual disability.
In the present study, rapamycin and everolimus, both as mTOR inhibitors, were investigated in models of kainic acid (KA)-induced seizure and lipopolysaccharide (LPS)-induced neuroinflammation.
In addition, focal cortical expression of mutant MTOR using in utero electroporation in mice, recapitulated the neuropathological features of FCDII, such as migration defect, cytomegalic neuron and spontaneous seizures.
Evidence from experimental research shows that encephalopathy in TSC might have a genetic cause, and mTOR activation caused by TSC gene mutation can be directly responsible for the early appearance of seizures and encephalopathy.
To investigate whether mammalian target of rapamycin complex 1 (mTORC1) inhibitors could reduce seizure frequency in children with tuberous sclerosis complex (TSC).
In a phase 1/2 clinical trial with 28 patients, clinically relevant reduction in overall seizure frequency was documented in individuals treated with the mTOR inhibitor everolimus.
Focal cortical expression of mutant MTOR by in utero electroporation in mice was sufficient to disrupt neuronal migration and cause spontaneous seizures and cytomegalic neurons.
Other mechanisms such as viral infections, prematurity, head trauma, and brain tumors are also posited. mTOR inhibitors (i.e., rapamycin) have shown positive results on seizure management in animal models and in a small cohort of patients with FCD.
Here we demonstrate that autophagy is suppressed in brain tissues of forebrain-specific conditional TSC1 and phosphatase and tensin homlog knock-out mice, both of which display aberrant mTOR activation and seizures.