Most cases of intractable childhood epilepsy are caused by malformations of the cerebral cortex known as cortical dysplasia. Currently, progress in understanding and treating cortical dysplasia is hindered by a lack of animal models that recapitulate key features of the disease, such as the presence of abnormal cell types, structural cortical abnormalities and seizures.
The molecular basis of most types of cortical dysplasia is unknown. Recent studies using human brain tissue suggest 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. Other studies support the notion that it is the dysplastic cells, or their faulty networks, that cause the seizures. This raises the possibility of using the mTOR inhibitor rapamycin as an antiepileptic treatment for patients with cortical dysplasia.
In this report, the authors characterize a conditional Pten knockout mouse as an animal model of cortical dysplasia. The Pten gene, which encodes a suppressor of the PI3K-mTOR pathway, was selectively disrupted in a subset of neurons. These mutant mice have several key features seen in cortical dysplasia, such as enlarged cortical neurons with increased mTOR activity, and abnormal electrographic activity with spontaneous seizures. Similar to patients with focal cortical dysplasia (FCD), the time of onset and the severity of the seizures varied. However, by 6 weeks of age, all mutant mice exhibited seizures and benefited from short-term treatment with the mTOR inhibitor rapamycin. This drug reduced the mTOR activity in the enlarged neurons, transiently reduced the size of the enlarged neurons, and strongly suppressed the severity and the duration of the epileptiform activity.
This paper presents a conditional Pten knockout mouse that is a novel model of cortical dysplasia. Furthermore, treatment of these mice with the drug rapamycin suppresses seizures. Previous studies in other seizure-prone mouse models have also demonstrated that treatment using either rapamycin or its analogues results in prolonged survival and improved neurological function. Together, these findings suggest that a limited modulation of mTOR activity may be sufficient to achieve long-lasting seizure control in some cortical dysplasia patients, especially those who are currently neither helped by available pharmacological treatments nor are suitable candidates for epilepsy surgery.
