Scientists at the Allen Institute and HHMI’s Janelia Research Campus have engineered a protein called iGluSnFR4 (“glue sniffer”).
It detects the faintest incoming signals between neurons, the release of glutamate, the brain’s most common neurotransmitter. Published in Nature Methods, this tool finally allows researchers to watch neurons receive information in real time.
Neurons receive thousands of tiny input signals and, based on those, generate an output that can form the basis of decisions, thoughts, or memories. By making these hidden inputs visible, researchers can begin to decode mysteries about how the brain works.
This breakthrough also opens important doors for medical research. Problems with glutamate signaling are connected to conditions such as Alzheimer’s, schizophrenia, autism, and epilepsy. With these sensors, scientists may be able to uncover the root causes of these disorders.
The discovery is equally valuable for drug development. Pharmaceutical companies can now test how new treatments affect actual synaptic activity, giving them a clearer picture of how medicines work in the brain and speeding up the search for better therapies.
Neurons communicate by sending electrical pulses that release chemical messengers, such as glutamate, across synapses. Each neuron receives thousands of inputs, and only specific patterns trigger it to fire, much like a complex domino chain.
Until now, these incoming signals were too faint and fast to detect in living brain tissue. The new discovery allows researchers to capture these inputs in real time, revealing the full conversation between neurons and unlocking the hidden language of the brain.
Kaspar Podgorski, Ph.D., a lead author on the study and senior scientist at the Allen Institute, said, “It’s like reading a book with all the words scrambled and not understanding the order of the words or how they’re arranged. I feel like what we’re doing here is adding the connections between those neurons and by doing that, we now understand the order of the words on the pages, and what they mean.”
“Neuroscientists have pretty good ways of measuring structural connections between neurons, and in separate experiments, we can measure what some of the neurons in the brain are saying, but we haven’t been good at combining these two kinds of information. It’s hard to measure what neurons are saying to which other neurons,” Podgorski added. “What we have invented here is a way of measuring information that comes into neurons from different sources, and that’s been a critical part missing from neuroscience research.”
With the new protein sensor iGluSnFR4 now available through Addgene, researchers around the world can begin exploring the brain’s hidden language. This tool allows researchers to see how neurons receive signals, opening the door to deeper insights into thought, memory, and emotion. By making faint, previously invisible whispers between brain cells clear and measurable, iGluSnFR4 has the potential to reshape neuroscience and transform how we understand the mind.
“The success of iGluSnFR4 stems from our close collaboration started at HHMI’s Janelia Research Campus between the GENIE Project team and Kaspar’s lab. That research has extended to the phenomenal in vivo characterization work done by the Allen Institute’s Neural Dynamics group,” said Jeremy Hasseman, Ph.D., a scientist with HHMI’s Janelia Research Campus. “This was a great example of collaboration across labs and institutes to enable new discoveries in neuroscience.”
Journal Reference:
- Aggarwal, A., Negrean, A., Chen, Y. et al. Glutamate indicators with increased sensitivity and tailored deactivation rates. Nat Methods (2025). DOI: 10.1038/s41592-025-02965-z
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