A Duke University Medical Center researcher who spent years looking for the signals that prompt the brain to form new connections between neurons has found one that may explain precisely how a well-known drug for epilepsy and pain actually works.
The finding may also point to new therapies for brain injury and neuropathic pain.
The role of neurons in the brain and nervous system is well known, but astrocytes, a different type of brain cell, still are largely a mystery. Duke scientist Cagla Eroglu, Ph.D. has discovered a receptor that receives messages from astrocytes so that the brain can form excitatory synapses, the cell-to-cell connections that can become overactive in conditions such as epilepsy. Working with a team of scientists from other institutions, Eroglu found this receptor is also blocked by the anti-convulsant drug gabapentin (Neurontin-).
The study will appear in the Oct. 16 issue of Cell.
"The study links astrocytes and their role in synapse formation to diseases, so if the normal process goes wrong, this may explain why people get epilepsy, why epilepsy gets worse, or why they have neuropathic pain," said Eroglu, assistant professor in the Duke Department of Cell Biology. "It's a fine balance, because synapse formation has to occur during development for neurons to transmit brain signals, but if this happens in an uncontrolled manner in the adult brain, it could lead to these debilitating conditions."
Eroglu spent years looking for this neuronal receptor, which prompts synapse formation. "The key clue came when we chopped thrombospondin, a protein that comes from astrocytes and triggers establishment of synapses, into small fragments and put it onto neurons. We found that a specific portion of thrombospondin, the EGF-like domain, was equally effective as the whole protein. This gave me the clue that was necessary to identify its neuronal receptor. However it took me a while to do so."
On advice she heard from a lecture by another scientist, Nobel laureate Linda Buck - "Spend more time thinking about your experiments and your results before designing new experiments" - Eroglu took a short break from her bench-work, went home, and reasoned her way through several possibilities, finally settling on the idea that a receptor for the molecule gabapentin might be a key to regulating the formation of synapses. Excited, she returned to the lab and verified the interaction between proteins. "When I discovered that gabapentin completely blocked synapse formation between isolated neurons, I could not sleep for days until I replicated the results."
The research also points to the need for further research on gabapentin's actions, Eroglu said. The drug gabapentin strongly blocks the receptor, reducing synapse formation in rodents.