Late stage mTOR inhibition is sufficient to reverse established epilepsy

Rajalaxmi Natarajan, PhD
Wed, 03/25/2015

Many pediatric cases of incurable epilepsy are attributed to a congenital defect, known as cortical dysplasia (CD) in which the neurons fail to migrate to appropriate locations in the brain during development. This results in abnormal brain architecture and neuronal miswiring that manifests as severe seizures. Currently, no treatments exist to prevent this condition and the only option is to reduce seizures using anticonvulsants or neurosurgery.

Several studies have implicated mutations in mechanistic target of rapamycin (mTOR) pathway genes in the pathogenesis of CD. mTOR pathway regulates crucial cellular processes and its hyperactivation is associated with many epileptic syndromes. In fact, in the recent years, rapamycin and its analogues have emerged as potential therapeutic agents for various mTOR- associated epileptic conditions.

Previous studies using newborn mice that mimic CD pathology show that rapamycin, an mTOR inhibitor is capable of short-term and long-term reversal of epileptic activity. It is important to note that these studies were conducted in newborn pups when the brain circuitry was still being established and epileptic episodes had just begun.

However, an important question that is clinically relevant and had not been addressed so far was – can intervention at later stages with rapamycin suppress chronic seizures and reverse severe neuropathological defects?

An exciting study1 published in Epilepsia by a team led by Dr. Anne Anderson, the medical director of Epilepsy Monitoring Unit at Texas Children’s hospital and associate professor of pediatrics at Baylor College of Medicine demonstrates that lowering mTOR hyperactivity in adult animals, after brain circuitry has fully developed, is sufficient to diminish epilepsy.

Lena Nguyen, a graduate student in Dr. Anderson’s lab and lead author of this study used fully grown mutant mice that have hyperactivated mTOR levels and share human CD pathologies such as enlarged neurons, disorganized neuronal architecture and severe seizures to address this question. They found that repeated rapamycin treatment of these mutant animals as adults was sufficient to reverse fully established epilepsy and other aberrant neuropathology.

Usually, only 30% of these mutant mice pups survive to adulthood. Interestingly, after rapamycin administration, >80% of young mutant mice survived to maturity.

Thus, this study provides preclinical evidence for mTOR inhibition as an effective therapy to combat late-stage severe epilepsy in a genetic model of CD. This study is opens the door to a tantalizing possibility that late-stage administration of mTOR inhibitors could reverse seizures and extend life span of human CD patients.


  1. Nguyen et al., Epilepsia, 2015, mTOR inhibition suppresses established epilepsy in a mouse model of cortical dysplasia

Learn More about Cortical Dysplasia

Resources for patients and families:

The Cortical Foundation
The Hemispherectomy Foundation

CMCD Foundation