Volume 16, Number 2
Looking Through the Keyhole
Sepkuty's glimpse of the synapse links cell biology and seizures.
But, by focusing purely on synapse biology, Sepkuty and his team are at least shedding light on the most common seizures: those that begin in the brain's hippocampus. They've created a basic flaw-in rats-that may help explain temporal lobe epilepsy.
On
a broader scale, the team's work advances a major concept in biology: that
synapses are truly dynamic and may be an unexpected site of brain regulation.
"Small adjustments that occur at the synaptic level could play a part in
keeping the brain on an even keel," says Sepkuty. Not long ago, Sepkuty began studies with Jeffrey Rothstein, M.D., Ph.D., a scientist intent on understanding the excitatory synapses involved in ALS and other neurodegenerative disease. Colleagues in Rothstein's lab pointed out animals that, every so often, would forsake their normal ratty endeavors to stand and stare for minutes at a time. The rats were engineered to lack a specific molecule-the EAAC1 transporter-that ferries excess neurotransmitter-in this case, glutamate-out of synapses and back into nerve cells.
But for these rats, neurodegeneration wasn't their problem. "Let's see if they're having seizures," Sepkuty proposed. He started recording rat EEGs. And it soon became clear that rat staring correlates with spiking. "It's similar to partial complex seizures in our patients, the sort that result in staring and confusion."
Sepkuty found that the fewer the transporter molecules in rats' neurons, the more frequent their seizures.
"That was intriguing," he says, "but didn't explain what was happening." So he turned for clues to see where glutamate transporters were situated. Yes, they dot the surface of excitatory neurons where they help recycle glutamate, an excitatory molecule. But transporters are also on inhibitory neurons, those that damp down activity of neighboring nerve cells.
Why? It turns out that glutamate is also a building block for the cell-quieting neurotransmitter GABA, the product of inhibitory neurons," says Sepkuty. "It's a new way of synthesizing GABA nobody knew about!"
A series of elegant experiments followed to show that tinkering with the supply of glutamate transporters could change the cells' supply of GABA.
"That got me really excited." Sepkuty knew they'd found a potential mechanism for seizures-not enough GABA-due to transporters gone awry. And that revealed a possible therapeutic target. Already, he says, he's blocked seizures in rats.
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