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Researchers at Cincinnati Children’s have discovered the first direct evidence that a biological mechanism long suspected in epilepsy is capable of triggering brain seizures – opening the door for studies to seek improved treatments and preventative therapies.
The study, published Sept. 19 in Neuron, reports that molecular disruptions in granule cells located in the dentate gyrus region of the brain caused brain seizures in mice similar to those seen in human temporal lobe epilepsy, one of the most common forms of the disorder.
“Epilepsy is one of those rare disorders where we have no real preventative therapies, and current treatments can have significant side effects,” says Steven Danzer, PhD, a neuroscientist in the Department of Anesthesia at Cincinnati Children’s and principal investigator on the study. “Establishing which cells and mechanisms are responsible for the seizures allows us to begin working on ways to control or eliminate the problem therapeutically, and in a more precise manner.”
Epilepsy can develop from a wide range of causes, including birth defects that disrupt normal brain development and serious brain injuries. Advances in genetically altering laboratory mice to mimic human disease made it possible to generate animals with a specific molecular disruption in dentate gyrus granule cells (DGCs). The dentate gyrus acts as a gate for excitatory signals in the brain, which can lead to seizures if not properly regulated.
The presence of abnormal DGCs in epilepsy has been observed for decades, although evidence linking them to seizures was lacking until the current study. Danzer and colleagues report that deleting the PTEN gene caused hyper-activation of the mTOR molecular pathway, which regulates cell growth and has been linked to tumor formation. This resulted in mice developing abnormal neural connections among their DGCs – similar to human temporal lobe epilepsy.
The animals experienced seizures even when the PTEN gene was deleted in less than 10 percent of the total DGC population. And when these mice were treated with rapamycin to block the mTOR pathway the seizures stopped.
Rapamycin has been tested successfully at Cincinnati Children’s to treat tuberous sclerosis, a disease that results in non-cancerous tumors forming around critical organs. Many people with tuberous sclerosis also develop epilepsy. Mutations involving PTEN and the mTOR pathway also have been identified in autism and schizophrenia, Danzer says.
“The profound impact of disrupting this pathway in just a small number of granule cells suggests that dentate may be a critical target for mTOR pathway mutations in other neurological diseases,” Danzer said. “We believe neuroscientists will be surprised by the huge impact of granule cell disruption.”
To follow up on the latest results, Danzer is studying whether eliminating abnormal DGCs will stop seizures in mice that already have epilepsy. Newer mTOR inhibitors also are being tested at Cincinnati Children’s to treat epilepsy.
Funding for the epilepsy study was provided by the National Institute of Neurological Disorders and Stroke (NINDS) and the Cincinnati Children’s Research Foundation. First author was Raymond Y.K. Pun, PhD, a researcher in the Department of Anesthesia.
Click on the image to enlarge and expanded caption.
Confocal microscopic images from the study in Neuron show the development of abnormal neural connections in dentate gyrus granule cell layers of the hippocampus of a mouse genetically altered to have epileptic seizures. Top images show the hippocampus. The lower images denote the dentate gyrus regions within the hippocampus.
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