Mutations in the catalytic subunit of phosphoinositide 3-kinase (PIK3CA) and other PI3K-AKT pathway components have been associated with cancer and a wide spectrum of brain and body overgrowth. In the brain, the phenotypic spectrum of PIK3CA-related segmental overgrowth includes bilateral dysplastic megalencephaly, hemimegalencephaly and focal cortical dysplasia, the most common cause of intractable pediatric epilepsy. We generated mouse models expressing the most common activating Pik3ca mutations (H1047R and E545K) in developing neural progenitors. These accurately recapitulate all the key human pathological features including brain enlargement, cortical malformation, hydrocephalus and epilepsy, with phenotypic severity dependent on the mutant allele and its time of activation. Underlying mechanisms include increased proliferation, cell size and altered white matter. Notably, we demonstrate that acute 1hour-suppression of PI3K signaling despite the ongoing presence of dysplasia has dramatic anti-epileptic benefit. Thus PI3K inhibitors offer a promising new avenue for effective anti-epileptic therapy for intractable pediatric epilepsy patients.
Animal experimentation: All animal experimentation done in this study was done in accordance with the guidelines laid down by the Institutional Animal Care and Use Committees (IACUC) of Seattle Children's Research Institute, Seattle, WA (protocol 14208), St. Jude Children's Research Hospital, Memphis, TN (protocol 278), Dana Farber Cancer Institute, Boston, MA (protocol 06-034).
- Sean J Morrison, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, United States
© 2015, Roy et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.