New imaging breakthrough sheds light on brain communication pathways

For the first time, scientists using cryo-electron microscopy have discovered the structure and shape of key receptors connecting neurons in the brain's cerebellum, which is located behind the brainstem and plays a critical role in functions such as coordinating movement, balance and cognition.

The research, published today in the journal Nature, provides new insight that could lead to the development of therapies to repair these structures when they are disrupted either by injury or genetic mutations affecting motor skills -- sitting, standing, walking, running, and jumping -- learning and memory.

The discovery by scientists at Oregon Health & Science University involves basic science research that won't immediately lead to a new pill or treatment but is an example of an American commitment to medical research sustained over decades to advance human health. Published in one of the world's most prestigious scientific journals, the new research was supported by the National Institutes of Health and the Howard Hughes Medical Institute.

The study reveals the organization of a specific type of glutamate receptor -- a chemical neurotransmitter that conveys signals between neurons and is considered the primary excitatory neurotransmitter in the brain -- bound together with proteins clustered on synapses, or junctions, between neurons in the cerebellum.

Synapses are crucial in all aspects of brain function, but the molecular structure has not been well understood in terms of how those pieces form together in a functional synapse. It's really critical to have receptors organized in exactly the right place so they can detect neurotransmitters released by an adjacent cell."

Eric Gouaux, Ph.D., senior author, senior scientist with the OHSU Vollum Institute

Examining glutamate in the cerebellum

Using OHSU's state-of-the-art cryo-electron microscopy, established as one of three national centers in 2018 and housed in the reinforced basement of a building on the university's South Waterfront Campus, researchers examined the shape of a particular kind of glutamate receptor in the cerebellum of rodents at near-atomic scale.

"We know if there is an injury or genetic mutation in the cerebellum, it can lead to devastating disorders of balance, movement or cognition," said co-author Laurence Trussell, Ph.D., professor of otolaryngology/head and neck surgery in the OHSU School of Medicine and a scientist in the Vollum Institute. "This kind of glutamate receptor seems to be really important in how the cerebellum works. It's entirely possible that developing drugs that target these receptors could improve its function."

Gouaux, an investigator with the Howard Hughes Medical Institute and the Jennifer and Bernard Lacroute Endowed Chair in Neuroscience Research at OHSU, said the new discovery could have applications for new treatments.

"We've been interested in this question about synapse engineering and molecular insight that may one day help to repair damaged synapses," he said. "This is a super exciting new direction with potential therapeutic applications."

Lead author Chengli Fang, Ph.D., a postdoctoral researcher in the Gouaux lab, conducted almost all of the experiments reported in the publication.

In addition to Gouaux, Trussell and Fang, co-authors include Cathy J. Spangler, Ph.D., Jumi Park, Ph.D., of OHSU; and Natalie Sheldon of OHSU and the Howard Hughes Medical Institute.

The research reported in this publication was supported by the National Cancer Institute, the National Institute of Neurological Disorders and Stroke, and the National Institute of Deafness and Other Communication Disorders, all of the National Institutes of Health, award numbers K00CA253730, R01NS038631, R35NS116798 and R01DC004450. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

All research involving animal subjects at OHSU must be reviewed and approved by the university's Institutional Animal Care and Use Committee, or IACUC. The IACUC's priority is to ensure the health and safety of animal research subjects. The IACUC also reviews procedures to ensure the health and safety of the people who work with the animals. The IACUC conducts a rigorous review of all animal research proposals to ensure they demonstrate scientific value and justify the use of live animals.