Basis for the epilepsy-autism connection is found – and may be reversible with an existing drug
May 2, 2012
Boston, Mass. – Early-life seizures are known to be associated with autism, and studies indicate that about 40 percent of patients with autism also have epilepsy. A study from Boston Children’s Hospital finds a reason for the link, and suggests that an existing drug, already shown to be safe in children, could help prevent autism from developing in newborns who have seizures. Findings were published May 2 in the online journal PLoS ONE.
Led by Frances Jensen, MD, in the Department of Neurology and the F.M. Kirby Neurobiology Center at Boston Children’s Hospital, the study suggests that seizures over-activate a biochemical pathway previously linked to autism, known as the mTOR pathway, and that this alters the fast-forming circuitry in infants’ developing brains.
In a rat model, Jensen and colleagues showed that early seizures not only resulted in epilepsy later in life, but also produced autistic-like behavior. They further showed that disabling the mTOR pathway – by giving the drug rapamycin before and after seizures – prevented development of abnormal patterns of connections (synapses) between brain cells, reduced later-life seizures and eased autistic-like symptoms.
“In children, there is overlap between epilepsy and autism, and epilepsy early in life has been linked to later autism,” says Jensen of Boston Children’s Hospital. “Our findings show one of probably many pathways that are involved in this overlap – importantly, one that is already a therapeutic target and where treatment can reverse the later outcome.”
Specifically, the study demonstrated that a group of signaling molecules known collectively as the mTOR pathway shows increased activation after a seizure. This increased signaling – above and beyond the surge that normally occurs early in life – disrupted the normal balance of synapse and circuit development to produce epilepsy and altered social behavior. Rapamycin treatment inhibited mTOR signaling, reducing susceptibility to seizures and preventing seizure-induced changes in the synapses.
The study uncovers a new link whereby epilepsy and autism may interact in early development. Last December, Jensen and colleagues published a related studyfinding that seizures exaggerated excitation and synaptic strengthening too soon in a rat model, causing synapses to lose their plasticity -- their ability to reconfigure in response to input from the outside world. When they gave the rats a drug called NBQX, which blocks receptors associated with excitation, these problems were reversed.
The mTOR pathway is already known to be over-active in tuberous sclerosis complex (TSC) a genetic disorder treated at Boston Children’s that often includes epilepsy and autism. The hospital is currently conducting a clinical trial of rapamycin in children with TSC.
“Our study suggests that even without tuberous sclerosis, seizures are inducing the mTOR pathway, and might on their own be contributing to the development of autism,” says Jensen. “It appears that blocking the mTOR pathway briefly after the initial seizures may reduce the risk of later epilepsy and autism. This research also suggests that the fields of epilepsy and autism may inform each other about new treatment targets.”
For further background, see this feature published last year in Nature Medicine.
Delia Talos, PhD, Hongyu Sun, MD, PhD, and Xiangping Zhou, MD, PhD, all of the Department of Neurology and Division of Neuroscience at Boston Children’s Hospital,shared first authorship on the paper. The study was funded by the National Institutes of Health, the National Institute of Child Health and Human Development, the Tuberous Sclerosis Alliance, the Ruth L. Kirschstein National Research Service Award and the Canadian Institutes of Health Research.
Boston Children’s Hospital is home to the world’s largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 1,100 scientists, including nine members of the National Academy of Sciences, 11 members of the Institute of Medicine and nine members of the Howard Hughes Medical Institute comprise Boston Children’s research community. Founded as a 20-bed hospital for children, Boston Children’s today is a 395 bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families. Boston Children’s also is the primary pediatric teaching affiliate of Harvard Medical School. For more information about research and clinical innovation at Boston Children’s, visit: http://vectorblog.org.