Scientists using cryo electron microscopy (cryo-EM) have revealed the structure of a critical receptor (AMPA) in the brain associated with learning, memory, behavior and mood. The research was also the first to reveal the structure of AMPA receptors in a natural state, a discovery that could lead to new insight about the mechanism behind a wide range of nervous system disorders and diseases.
“These are the fundamental electrical switches of the brain,” says senior author Eric Gouaux, chair of neuroscience in the Oregon Health and Science University Vollum Institute and an investigator for the Howard Hughes Medical Institute. “If these switches don’t work right, then the brain doesn’t function. It can lead to seizures, memory loss and neurodegenerative conditions like Alzheimer’s disease.”
Researchers at OHSU and the US Department of Energy’s Pacific Northwest National Laboratory used cryo-EM and targeted mass spectrometry to reveal the architecture and subunit arrangement of AMPA receptors in rodents. AMPA receptors are activated by the neurotransmitter glutamate, forming permeable ion channels that carry signals between cells throughout the nervous system.
By discerning the makeup of the working structure in rodents, scientists can isolate the same structures in post-mortem samples of human brains and make comparisons. The team may then be able to determine differences between the structure and organization of healthy AMPA receptors and those in people with neurodegenerative diseases.
In fact, Gouaux’s researchers at OHSU intend to do exactly that. “It’s super exciting,” he says. “There is no guarantee, but what we want to do is understand how these receptors are different in devastating human diseases for which there are presently few, if any, treatments. If we can get new insights about the mechanism of the disease, it could provide novel approaches for therapies.”
The ability to use cryo-EM vastly improves scientific ability to discern individual receptors within a true natural, or native, state. Gouaux previously relied on X-ray crystallography to visualize important structures in the central nervous system, however that technique requires scientists to stack up vast quantities of identical molecules so they can be crystallized to form an artificial picture of their native structure.
Cryo-EM enables scientists to see molecules in near-atomic detail. “It’s a sensitive technique where you need only a small number of molecules,” Gouaux said. “Now we can examine the true receptor as it exists in its natural state.”