Surprise, surprise, surprise: Hopkins scientists unexpectedly create epilep...( s Hopkins. Previously only glutamate m...)

s Hopkins. Previously, only glutamate made inside the cell - rather than brought into it - was thought to contribute to GABA manufacture. While glutamate transport problems may not contribute to human epilepsy, the finding may lead to new ways to treat it. Getting more glutamate into GABA-producing neurons may help calm the excessive electrical firing of brain cells, says Rothstein.

In rats, the glutamate transporter EAAC1 is the main mover, getting the molecule into and out of brain cells and maintaining the appropriate levels of the excitatory chemical. By giving the rats pieces of RNA that complement EAAC1's message, the scientists were able to gradually reduce the amount of EAAC1 the cells produced.

"The RNA binds to EAAC1's message like a zipper, keeping it tied up," says Rothstein. "The transporter stops working because instructions for making new EAAC1 protein aren't available, but normal degradation of existing EAAC1 protein continues."

In the brains of the rats, GABA production was slowed, and levels of the chemical were cut in half in specific areas of the brain compared to normal animals. Studying the electrical activity of the brain revealed rapid spikes at the same time as freezing and staring episodes - "textbook epileptic seizures," says Rothstein.

"Despite recognizing that glutamate and GABA have the same functions in many creatures, no one had established a clean link between the pathways that use them," says Rothstein. "This glutamate transporter, EAAC1, is central to the production of GABA in the normal rat brain, and its human counterpart likely has the same role." Others have shown that knockout mice, which lack the gene and its product throughout development, do not develop epilepsy. Rothstein suggests knockout mice may recruit other glutamate transporters to compensate for the lack of EAAC1 during early development and use them in its place throughout their lives. Adult animals likely
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Contact: Joanna Downer
jdowner1@jhmi.edu
410-614-5105
Johns Hopkins Medical Institutions
2-Aug-2002

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