Epilepsy may be sparked by a metal imbalance in the brain caused by a singlegene mutation, a study in mice suggests. The finding could help develop new treatments in humans who suffer from the condition.
Steven Clapcote's team at the University of Leeds, UK, pinpointed a gene that seems to play an important part in the genesis of epileptic seizures, which result from abnormal bursts of electrical activity in the brain and can occur even when there is no underlying neurological condition.
The Atp1a3 gene is one of three that produce a chemical pump mechanism to keep sodium and potassium levels in brain nerve cells and the surrounding tissue at the levels needed for normal activity.
"It's been known for a long time that injecting the sodium/potassium pump inhibitor ouabain into the brain can induce seizures in rats," says Clapcote, and it's also known that mice lacking two of three forms of the pump – either the "alpha1" or "alpha2" forms – are free from seizures.
Cured offspring
Clapcote's team have now determined that mice with a mutated copy of theAtp1a3 gene and reduced activity of the "alpha3" pump were prone to epileptic seizures. The mouse strain has been dubbed Myshkin after a Dostoevsky character in The Idiot, who suffered from epilepsy. "Mysh" also comes from the Russian for mouse.
The team could treat some of the symptoms in the Myshkin mice with valproic acid, a standard epilepsy treatment. But the researchers found they could also prevent seizures from occurring completely – at least in the next generation.
They injected DNA fragments containing the normal Atp1a3 gene into mouse eggs to establish a second strain of mice that produced extra copies of the normal alpha3 pump, and crossed them with the Myshkin mice.
"Half of the offspring of this cross had the faulty alpha3 gene from the Myshkin parent," he says. "However, they did not have epilepsy because they also inherited the extra copies – we didn't work out how many – of the normal alpha3 gene from the other parent."
'Ideal tool'
The mouse and human version of the Atp1a3 gene are almost identical, and Clapcote thinks it is a "strong candidate" gene to explain some forms of human epilepsy.
Working with colleagues at the University of Swansea, UK, the researchers have begun to screen DNA from people with epilepsy to search for mutations in the gene. If there's a positive match, the Myshkin mice would be an ideal tool to help in the development and testing of new epilepsy therapies, Clapcote says.
Journal reference: Proceedings of the National Academy of Sciences (DOI: 10.1073/pnas.0904817106)
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