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PET image

Brighter areas in positron emission tomography scans targeting synaptic vesicle glycoprotein 2A show precisely where neurons are communicating.

Yale PET Center

Watching neurons talk in a living brain

Ever wonder what it looks like when brain cells chat up a storm? Researchers have found a way to watch the conversation in action without ever cracking open a skull. This glimpse into the brain’s communication system could open new doors to diagnosing and treating disorders from epilepsy to Alzheimer’s disease.

Being able to see where—and how—living brain cells are working is “the holy grail in neuroscience,” says Howard Federoff, a neurologist at Georgetown University in Washington, D.C., who was not involved with the work. “This is a possible new tool that could bring us closer to that.”

Neurons, which are only slightly longer than the width of a human hair, are laid out in the brain like a series of tangled highways. Signals must travel down these highways, but there’s a catch: The cells don’t actually touch. They’re separated by tiny gaps called synapses, where messages, with the assistance of electricity, jump from neuron to neuron to reach their destinations.

The number of functional synapses that fire in one area—a measure known as synaptic density—tends to be a good way to figure out how healthy the brain is. Higher synaptic density means more signals are being sent successfully. If there are significant interruptions in large sections of the neuron highway, many signals may never reach their destinations, leading to disorders like Huntington disease.

The only way to look at synaptic density in the brain, however, is to biopsy nonliving brain tissue. That means there’s no way for researchers to investigate how diseases like Alzheimer’s progress—something that could hold secrets to diagnosis and treatment.

To remedy this, a team of Yale University scientists have developed a surgery-free technique to view how well neurons are talking to one another, as they report today in Science Translational Medicine. They call it “synaptic density imaging.”

The approach uses a radioactive molecule that, when applied to brain tissue, selectively latches on to certain membranes. When paired with positron emission tomography (PET), a scan that measures nuclear radiation given off by the molecule, the chosen areas light up on the image of the organ being studied. The brighter the light, the more glucose—or energy—used by those cells. When applied to synapses, the technique should be able to tell whether a message is successfully jumping from one neuron to another. Multiply that by the 100 trillion synapses in the brain, and you’ve got an accurate picture of synaptic density.

The team intravenously injected a radioactive molecule into baboons, hoping it would stick to a membrane protein in the brain called synaptic vesicle glycoprotein 2A (SV2A for short). SV2A molecules usually hang out near the ends of neurons where messages are received, so it would theoretically light up on a PET scan when a message makes its synaptic jump. After comparing PET scan images of SV2A in the baboon brains to autopsies, the researchers decided SV2A was indeed an accurate marker for synaptic density. Now that they had their marker, they could potentially tell whether some areas of the brain were affected by disorders like Parkinson’s: A lack of synaptic firing would cause those areas to come up dark on the PET scan.

To confirm the results in humans, the researchers used synaptic density imaging to look at the brains of people with temporal lobe epilepsy. The condition causes seizures through the loss of synaptic firing in the same area every time. In their experiment, the scientists correctly predicted the precise areas of the brain that came up dark on the PET scan—the areas that had lost synaptic density.

The researchers hope the technique can be used to follow a neurological disorder over a patient’s lifetime to show not just where synapses are failing to fire, but also whether medications are restoring those synapses’ functionality.

Federoff is excited about the new technique, but he says more work needs to be done to determine just how accurate and consistent the approach is. That will require looking at people in different age groups and with varying brain conditions, he says. “This could very well be another tool in the everyday clinical evaluation toolbox.”