Researchers 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 a major complications of TSC in children.
The research, conducted at Washington University School of Medicine in St. Louis, represents one of the first animal models of epilepsy that does not require toxic injections or injury and results from a single gene defect.
Professor of Neurology, Dr David H Gutmann, said:
"What's enormously exciting about this study is the potential to employ this mouse model as a pre-clinical model for TSC-related epilepsy. 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."
Around 1 in 7,000 people have TSC, which is a genetic disorder, with seizures occurring in over 50 per cent of people with the disorder. TSC also causes tumours 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 tumours, Gutmann's team hypothesised that TSC1 may provide a clue into tumour 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 tumours; 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, behaviours 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 organised collections of neurons in the hippocampus – a region involved in human epilepsy.
Associate professor of neurology and paediatrics Dr Kelvin Yamada said:
"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."
The research appears online July 18 in the Annals of Neurology and will be published in the September issue of the journal.