Nearly three decades ago there was a revolution in treatment for depression, as scientists began to manipulate serotonin levels in the brain with drugs such as Prozac.
But serotonin is only a bit-player in the brain’s chemistry, representing less than one percent of the signaling chemicals, or neurotransmitters, that make things happen in our brain.
The real leader is glutamate, which is responsible for 90 percent of synaptic connections in the brain and enables major functions such as memory, learning and cognition. Yet remarkably we know very little about how glutamate works. In fact, for seventy years researchers didn’t even realise that it had a role in the nervous system.
Dr Brian Billups, a neuroscientist at The John Curtin School of Medical Research is turning this around by studying the basic mechanisms involved in glutamate recycling and production, and helping to unravel our understanding of diseases like epilepsy.
“It’s amazing we don’t know this already. It feels like the big unanswered question,” says Dr Billups.
Neurotransmitters are chemical messengers which communicate between neurons or nerve cells. Neurons form the basic working unit of the brain and are connected to each other via synapses, which are contact points that connect neurons to each other.
“Most brain synapses release the neurotransmitter glutamate. Despite its ubiquitous nature, very little is known about how presynaptic terminals recycle or otherwise replace the released glutamate,” says Dr Billups.
Glutamate might be ubiquitous but it is also vital to have just the right amount. It is essential for all brain functions, and if you don’t have enough it will result in memory loss and cognitive decline. But if you if you have too much, it can result in the seizures and cell death that occur in epilepsy.
This delicate balance is achieved via glutamate-glutamine recycling. Glutamate is stored in a chemically inactive form called glutamine, which can be quickly activated and deactivated as needed.
“We are looking at the basic biological mechanism involved,” says Dr Billups.
Dr Billups and his colleagues discovered that glutamate production is related to transport of glutamine from the presynaptic terminal.
Dr Billups was able, for the first time, to observe glutamine being converted to glutamate by a synapse. He found the trigger was a tiny electrical pulse that occurs at the individual synapse, only one or two microns across.
Understanding what triggers glutamine to be converted into glutamate is one of the first steps to understanding diseases such as epilepsy, which has been linked to elevated levels of glutamate.
“If we understand the mechanisms involved in glutamate recycling, it will help to identify possible future drugs for conditions such as epilepsy,” says Dr Billups.
Epilepsy affects over two-hundred thousand people in Australia. A third of those can’t be treated with drugs currently available.
“There is a big need for new drugs for these people who can’t be helped,” says Dr Billups.
“Ultimately if it helps some people with a debilitating condition—that’s important”.
Published in Research Highlights – The John Curtin School of Medical Research, ANU, May 2017.
Rebecca Blackburn 