Brain Channels “Stopped in Time” Reveal How We Think and Learn

Scientists used advanced cryo-EM imaging to reveal how glutamate activates brain receptors, paving the way for new neurological treatments.

To better understand how brain cells communicate using chemical signals, scientists have used a highly specialized microscope to capture detailed images of how glutamate, one of the brain’s most common signaling molecules, activates a channel that allows charged particles to flow into cells. This breakthrough, led by researchers at Johns Hopkins Medicine, reveals new insights into how these channels function and could help guide the development of drugs that either block or activate them to treat conditions such as epilepsy and certain intellectual disabilities.

The study, conducted in collaboration with scientists at UTHealth Houston and funded by the National Institutes of Health, was published on March 26 in the journal Nature.

“Neurons are the cellular foundation of the brain, and the ability to experience our environment and learn depends on [chemical] communications between neurons,” says Edward Twomey, Ph.D., assistant professor of biophysics and biophysical chemistry at the Johns Hopkins University School of Medicine.

Scientists have long known that a major molecule responsible for neuron-to-neuron communications is the neurotransmitter glutamate, a molecule abundant in the spaces between neurons. Its landing place on neurons is a channel called an AMPA receptor, which interacts with glutamate, and then acts like a pore that takes in charged particles. The ebb and flow of charged particles creates electrical signals that form communications between neurons.

Advanced Microscopy Captures Molecular Movements

To figure out details of the minuscule movements of AMPA receptors (at the level of single atoms), researchers used a very high-powered microscope to image these channels during specific steps in the communications processes. For the study, the scientists used a cryo-electron microscope (cryo-EM) in a facility at the Johns Hopkins University School of Medicine.

Typically, scientists find it easier to study cell samples that are chilled, a state that provides a stable environment. But at normal body temperature, Twomey’s team found that the AMPA receptors and glutamate activity increased, providing more opportunities to capture this process in cryoEM images.

To that end, the scientists purified AMPA receptors, taken from lab-grown human embryonic cells that are used widely in neuroscience research to produce such proteins. Then, they heated the receptors to body temperature (37 degrees Celsius or 98.6 degrees Fahrenheit) before exposing them to glutamate. Immediately after this, the receptors were flash-frozen and analyzed with cryoEM to get a snapshot of the AMPA receptors bound to the major signaling molecule, glutamate.

After assembling more than a million images taken with cryoEM, the team found that glutamate molecules act like a key that unlocks the door to the channel, enabling it to open more widely. This occurs by the clamshell-like structure of the AMPA receptor closing around glutamate, an action that pulls open the channel below.

Implications for Drug Development

Twomey’s previous research has shown that drugs such as perampanel, used to treat epilepsy, act as a door stopper around the AMPA receptor to limit the channel from opening and reducing the abundance of activity known to happen in brain cells of people with epilepsy.

Twomey says the findings could be used to develop new drugs that bind to AMPA receptors in different ways that either open or close the signaling channels of brain cells.

“With each new finding, we are figuring out each of the building blocks that enable our brains to function,” says Twomey.

Reference: “Glutamate gating of AMPA-subtype iGluRs at physiological temperatures” by Anish Kumar Mondal, Elisa Carrillo, Vasanthi Jayaraman and Edward C. Twomey, 26 March 2025, Nature.
DOI: 10.1038/s41586-025-08770-0

Additional scientists who contributed to the work are Anish Kumar Mondal from Johns Hopkins and Elisa Carrillo and Vasanthi Jayaraman from UTHealth Houston.

Funding for the research was provided by the National Institutes of Health (R35GM154904, R35GM122528), the Searle Scholars Program and the Diana Helis Henry Medical Research Foundation.

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