Malformations of the cerebral cortex known as
cortical dysplasia account for the majority of cases of intractable childhood
epilepsy. With the exception of the
tuberous sclerosis complex, the molecular basis of most types of
cortical dysplasia is completely unknown. Currently, there are no good animal models available that recapitulate key features of the disease, such as structural cortical abnormalities and
seizures, hindering progress in understanding and treating
cortical dysplasia. At the neuroanatomical level, cortical abnormalities may include dyslamination and the presence of abnormal cell types, such as enlarged and misoriented neurons and neuroglial cells. Recent studies in resected human brain tissue suggested that a misregulation of the PI3K (phosphoinositide 3-kinase)-Akt-mTOR (
mammalian target of rapamycin) signaling pathway might be responsible for the excessive growth of dysplastic cells in this disease. Here, we characterize neuronal subset (NS)-Pten mutant mice as an animal model of
cortical dysplasia. In these mice, the Pten gene, which encodes a suppressor of the PI3K pathway, was selectively disrupted in a subset of neurons by using Cre-loxP technology. Our data indicate that these mutant mice, like
cortical dysplasia patients, exhibit enlarged cortical neurons with increased mTOR activity, and abnormal electroencephalographic activity with spontaneous
seizures. We also demonstrate that a short-term treatment with the mTOR inhibitor
rapamycin strongly suppresses the severity and the duration of the seizure activity. These findings support the possibility that this
drug may be developed as a novel
antiepileptic treatment for patients with
cortical dysplasia and similar disorders.