Journal Article

Mouse models of human PIK3CA-related brain overgrowth have acutely treatable epilepsy

Skibo, Jonathan, Kalume, Franck, Ni, Jing, Rankin, Sherri, Roy, Achira, Zhao, Jean J, Lu, Yiling, Mills, Gordon B, Dobyns, William B, Baker, Suzanne J, Millen, Kathleen J

2015

Overview

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 1 hr-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. An enzyme called PI3K is involved in a major signaling pathway that controls cell growth. Mutations in this pathway have devastating consequences. When such mutations happen in adults, they can lead to cancer. Mutations that occur in embryos can cause major developmental birth defects, including abnormally large brains. After birth, these developmental problems can cause intellectual disabilities, autism and epilepsy. Children with this kind of epilepsy often do not respond to currently available seizure medications. There are several outstanding questions that if answered could help efforts to develop treatments for children with brain growth disorders. Firstly, how do the developmental abnormalities happen? Do the abnormalities themselves cause epilepsy? And can drugs that target this pathway, and are already in clinical trials for cancer, control seizures? Now, Roy et al. have made mouse models of these human developmental brain disorders and used them to answer these questions. The mice were genetically engineered to have various mutations in the gene that encodes the catalytic subunit of the PI3K enzyme. The mutations were the same as those found in people with brain overgrowth disorders, and were activated only in the developing brain of the mice. These mutations caused enlarged brain size, fluid accumulation in the brain, brain malformations and epilepsy in developing mice – thus mimicking the human birth defects. The severity of these symptoms depended on the specific mutation and when the mutant genes were turned on during development. Next, Roy et al. studied these mice to see if the seizures could be treated using a drug, that has already been developed for brain cancer. This drug specifically targets and reduces the activity of PI3K. Adult mutant mice with brain malformations were treated for just one hour; this dramatically reduced their seizures. These experiments prove that seizures associated with this kind of brain overgrowth disorder are driven by ongoing abnormal PI3K activity and can be treated even when underlying brain abnormalities persist. Roy et al. suggest that drugs targeting PI3K might help treat seizures in children with these brain overgrowth disorders.

• Publisher: eLife Science Publications, Ltd,eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Analysis / Animals / Birth defects / BKM120 / Brain / Brain - pathology / Class I Phosphatidylinositol 3-Kinases / cortical dysplasia / Disease Models, Animal / Dysplasia / Enzymes / Epilepsy / Epilepsy - genetics / Epilepsy - pathology / Gene mutations / Genetically modified organisms / Human Biology and Medicine / Humans / megalencephaly / Megalencephaly - complications / Megalencephaly - genetics / Megalencephaly - pathology / Mice / mouse models / Mutant Proteins - genetics / Mutation, Missense / Neuroscience / Pediatrics / Phosphatidylinositol 3-Kinases - genetics / PI3K / Seizures (Medicine)