July 19, 2002 St. Louis, July 18, 2002 -- Researchers at Washington University School of Medicine in St. Louis have developed a mouse model of the genetic disorder tuberous sclerosis complex (TSC). The mice develop epilepsy within the first few months of life, mimicking one of the most devastating complications of TSC in children.
This research represents one of the first animal models of epilepsy that does not require toxic injections or injury and results from a single gene defect. It appears online July 18 in the Annals of Neurology and will be published in the September issue of the journal.
"What's enormously exciting about this study is the potential to employ this mouse model as a pre-clinical model for TSC-related epilepsy," says David H. Gutmann, M.D., Ph.D., the Donald O. Schnuck Family Professor of Neurology. "In addition, we disrupted a gene for TSC in one of the brain's support cells, called astrocytes, instead of in the brain's main communication cells, neurons. Our results therefore shed light on the contribution of cells other than neurons to the development of seizures and epilepsy."
Gutmann led the study in conjunction with Kelvin Yamada, M.D., associate professor of neurology and pediatrics.
TSC is a genetic disorder that affects about 50,000 Americans, more than half of whom experience frequent, debilitating epileptic seizures. TSC also causes tumors to form in various organs, including the brain. Physicians cannot cure the disease nor can they predict which individuals will experience severe symptoms.
Scientists have identified two genes responsible for TSC – TSC1 and TSC2. Because affected individuals often develop brain tumors, Gutmann's team hypothesized that TSC1 may provide a clue into tumor development. Since mice that completely lack TSC1 die early in development, the researchers engineered a strain of animals that are missing the TSC1 gene in only one type of brain cell – astrocytes. Surprisingly, the mice did not develop tumors; instead, they developed epilepsy.
Mice without astrocyte TSC1 began exhibiting abnormal movements and posture around two months after birth. They occasionally became rigid, fell over and began to shake their heads and limbs, behaviors characteristic of seizures. To see if these episodes were in fact seizures, the team recorded brain activity in affected animals and in normal mice using electroencephalography (EEG). EEG recordings verified that the affected mice had frequent seizures and the normal mice did not.
Moreover, brain slices from these mice lacking TSC1 in astrocytes revealed other abnormalities. The animals had larger brains with far more astrocytes. Most surprisingly, deleting TSC1 in astrocytes evoked changes in another type of brain cell – neurons. Within the first five weeks after birth, mice had abnormally organized collections of neurons in the hippocampus – a region involved in human epilepsy.
"In our model, the loss of TSC1 expression in astrocytes translated over time into defects in neuronal function and eventually led to epilepsy in mice," says Yamada. "We're very excited about this discovery because it may help us understand how seizure disorders develop, both in TSC and in other kinds of epilepsy."
Uhlmann EJ, Wong M, Baldwin RL, Bajenaru ML, Onda H, Kwiatkowski DJ, Yamada K, Gutmann DH. Astrocyte-specific TSC1 conditional knockout mice exhibit abnormal neuronal organization and seizures. Annals of Neurology, 52(3), September 2002.
Funding from the Tuberous Sclerosis Alliance and the National Institutes of Health supported this research.
The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.
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