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Hypervascularization in mTOR ‐dependent focal and global cortical malformations displays differential rapamycin sensitivity
Author(s) -
Zhang Longbo,
Huang Tianxiang,
Teaw Shan,
Bordey Angélique
Publication year - 2019
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.15969
Subject(s) - tuberous sclerosis , sirolimus , pi3k/akt/mtor pathway , epilepsy , forebrain , tsc2 , medicine , pathology , endocrinology , biology , neuroscience , microbiology and biotechnology , signal transduction , central nervous system
Objectives Patients with mammalian target of rapamycin (mTOR) –dependent malformations of cortical development ( MCD s) associated with seizures display hyperperfusion and increased vessel density of the dysmorphic cortical tissue. Some studies have suggested that the vascular defect occurred independently of seizures. Here, we further examined whether hypervascularization occurs in animal models of global and focal MCD with and without seizures, and whether it is sensitive to the mTOR blocker, rapamycin, that is approved for epilepsy treatment in tuberous sclerosis complex. Methods We used two experimental models of mTOR ‐dependent MCD consisting of conditional transgenic mice containing Tsc1 null 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. Alterations in blood vessels and the effects of a 2‐week–long rapamycin treatment on these phenotypes were assessed in juvenile mice. Results Blood vessels in both the focal and global MCD s of postnatal day 14 mice displayed significant increase in vessel density, branching index, total vessel length, and decreased tissue lacunarity. In addition, rapamycin treatment (0.5 mg/kg, every 2 days) partially rescued vessel abnormalities in the focal MCD model, but it did not ameliorate the vessel abnormalities in the global MCD model that required higher rapamycin dosage for a partial rescue. Significance Here, we identified hypervascularization in mTOR ‐dependent MCD in the absence of seizures in young mice, suggesting that increased angiogenesis occurs during development in parallel to alterations in corticogenesis. In addition, a predictive functional outcome is that dysplastic neurons forming MCD will have better access to oxygen and metabolic supplies via their closer proximity to blood vessels. Finally, the difference in rapamycin sensitivity between a focal and global MCD suggest that rapamycin treatment will need to be titrated to match the type of MCD .