Summary: For years, scientists have used mRNA levels as a “blueprint” to estimate which proteins the brain is making. However, reveals that this blueprint is often misleading. Using a revolutionary technology called Ribo-STAMP, researchers have created the first high-resolution map of actual protein production—known as translation—across 20,000 individual cells in the mouse hippocampus.
The findings show that brain cells don’t always follow their genetic instructions; some “memory neurons” churn out proteins at massive rates while others stay quiet, even when their mRNA levels are identical. This discovery offers a new way to investigate why translation goes wrong in neurological conditions like autism and Fragile X syndrome.
Key Facts
- The “Ribo-STAMP” Breakthrough: This technology fuses an editing enzyme to ribosomes (the cell’s protein-makers), allowing scientists to “tag” and track exactly which proteins are being manufactured in real-time.
- Translation Disconnect: mRNA levels are often a poor predictor of protein production in the brain, as neurons frequently store mRNA for later use rather than translating it immediately.
- Memory Neuron Disparity: While CA1 and CA3 pyramidal neurons look similar, CA3 neurons produce proteins at significantly higher rates, suggesting they play a more “high-energy” role in memory circuits.
- Isoform Influence: The study found that different versions of the same gene (isoforms) can drastically change how much protein is made, providing a potential link between genetic variations and brain disease.
- High vs. Low States: Individual neurons can exist in different “gears”—high-translation states for active communication and low-translation states for resting periods.
Source: UCSD
The brain’s ability to do everything from forming memories to coordinating movement relies on its cells producing the right proteins at the right time. But directly measuring this protein production, known as translation, across different types of brain cells has been a challenge.
Now, scientists at University of California School of Medicine, Scripps Research and their colleagues have developed a technology that reveals which proteins are generated by individual brain cells.
The team used their method — called Ribo-STAMP — to create the first maps of protein production across nearly 20,000 individual cells in the mouse hippocampus, a brain region essential for learning and memory.
The study was published on February 18, 2026 in Nature.
“We think this technology will let the field revisit whether neurological conditions, including autism spectrum disorder, fragile X syndrome and tuberous sclerosis complex are caused by defects in translation,” says co-corresponding author Gene Yeo, PhD, professor of cellular and molecular medicine at UC San Diego School of Medicine and founding director of the Center for RNA Technologies and Therapeutics.
In all cells, DNA is first transcribed into messenger RNA (mRNA), a temporary copy of DNA that can travel to the protein-making machinery inside cells. There, the code is translated into proteins, the molecules that perform most cellular functions.
Scientists frequently measure mRNA levels as a proxy for which proteins are being made in a cell. But in brain cells, there’s a large disconnect between mRNA levels and proteins. Rather than being quickly turned into proteins, mRNA is often stored in the long spindly arms of neurons, produced in advance and ready when needed.
“It’s been difficult to measure mRNA translation in single cells, despite the field of single cell transcriptomics expanding across tissues, conditions and diseases,” says Yeo, who is also director of the UC San Diego Sanford Stem Cell Institute Innovation Center. “We developed this technology in hopes that it will lead to a more complete picture.”
Yeo’s team had previously developed Ribo-STAMP to directly measure protein production in cells. The method works by fusing a molecular editing enzyme to ribosomes — the molecular machines that carry out translation. As ribosomes translate each mRNA molecule into protein, the enzyme makes nucleotide changes to the RNA strand. Scientists can then use standard RNA sequencing to identify which RNAs were changed.
In the current study, the researchers applied Ribo-STAMP to the brain for the first time. The team focused on the hippocampus, in part because it’s already well-studied and the results could be verified.
“This gave us an entirely different angle to look at the hippocampus, and we found a lot of new and exciting things,” said co-corresponding author Giordano Lippi, associate professor of neuroscience at Scripps Research. “This sort of foundational work is needed to eventually understand what goes wrong at the onset of brain diseases.”
When they measured translation in nearly 20,000 individual cells in the mouse hippocampus, they observed some unexpected patterns beyond what was known.
One of the most surprising findings came from comparing two types of neurons critical for memory: CA1 and CA3 pyramidal cells. Despite their similar roles in memory circuits, CA3 neurons showed much higher rates of protein production than CA1 neurons.
The findings not only reveal that the pyramidal cell types are less similar than previously believed, but they also suggest an important role for translation in how circuits in the brain coordinate memory.
This study also indicated how different mRNA molecules made from the same gene, known as isoforms, affect how much of the corresponding protein is produced. The researchers, including co-first authors Samantha Sison and Eric Kofman at UC San Diego School of Medicine, and Federico Zampa at Scripps Research, discovered that in hippocampal neurons, isoforms with longer regulatory regions tended to be translated into proteins at a higher rate. Understanding this link better could shed light on how variations in mRNA transcripts could contribute to disease.
“Previous work has shown how changes in isoform expression strongly correlates with neurological disorders, but the reason behind that hasn’t been well-understood,” says Lippi.
“Our work suggests that if cells prefer one isoform over another, they may actually be changing protein levels.”
Beyond differences between cell types, the researchers discovered that individual neurons can exist in “high” and “low” translation states, producing proteins at dramatically different rates.
Neurons in the high translation state tended to make proteins involved in communication between neurons and energy production, hinting that translation states might distinguish more active neurons from quieter ones.
Yeo said that their dataset on the brain’s “translatome” — the full set of mRNAs that are translated into proteins — is just the beginning of a new understanding of how healthy brain cells coordinate protein production, and what that means for disease.
Additional co-authors on the study include Pratibha Jagannatha, Grady Nguyen, Jack Naritomi, Chun-Yuan Chen, Orel Mizrahi, Steven Blue and Ryan Marina at UC San Diego; Su Yeun Choi, David Sievert, Sourish Mukhopadhyay, Dong Yang, Cailynn Wang, Zhengyuan Pang and Li Ye at Scripps Research; Asa Shin, Akanksha Khorgade and Aziz Al’Khafaji at The Broad Institute of MIT and Harvard; Wenhao Jin at Sanford Laboratories; and Kristopher Brannan at Houston Methodist Research Institute.
Funding: The study was funded, in part, by grants from the National Institutes of Health (grants MH126719, NS121223, EY031597, HG011864, NS103172, HG004659, HG009889 and HG010646).
Key Questions Answered:
A: Much of our current understanding of brain disease is based on “transcriptomics” (measuring mRNA). This study doesn’t invalidate that work, but it adds a missing layer. It shows that two cells might have the same mRNA “potential” but very different “actual” protein outputs.
A: The researchers found that CA3 neurons are much more active protein-makers than CA1 neurons. This suggests that the CA3 region might be the “heavy lifter” in the hippocampus, requiring more protein synthesis to maintain the complex circuits needed for memory storage.
A: Many conditions like autism and Fragile X are thought to be “translation diseases”—where the brain makes too much or too little of certain proteins. Ribo-STAMP finally gives scientists a tool to see exactly where that process breaks down at a single-cell level.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this genetics and neuroscience research news
Author: Susanne Bard
Source: UCSD
Contact: Susanne Bard – UCSD
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Single-cell and isoform-specific translational profiling of the mouse brain” by Samantha L. Sison, Federico Zampa, Eric R. Kofman, Su Yeun Choi, Pratibha Jagannatha, Grady G. Nguyen, Jack T. Naritomi, Asa Shin, Akanksha Khorgade, Wenhao Jin, Chun-Yuan Chen, David M. Sievert, Sourish Mukhopadhyay, Orel Mizrahi, Steven M. Blue, Ryan J. Marina, Dong Yang, Cailynn C. Wang, Zhengyuan Pang, Kristopher W. Brannan, Li Ye, Aziz M. Al’Khafaji, Gene W. Yeo & Giordano Lippi . Nature
DOI:10.1038/s41586-026-10118-1
Abstract
Single-cell and isoform-specific translational profiling of the mouse brain
The brain displays the richest repertoire of post-transcriptional mechanisms regulating mRNA translation. Among these, alternative splicing has been shown to drive cell-type specificity and, when disrupted, is strongly linked to neurological disorders.
However, genome-wide measurements of mRNA translation with isoform sensitivity at single-cell resolution have not been achieved. To address this, we deployed Surveying Ribosomal Targets by APOBEC-Mediated Profiling (Ribo-STAMP) coupled with short-read and long-read single-cell RNA sequencing in the brain.
We generated the first isoform-sensitive single-cell translatomes of the mouse hippocampus at postnatal day 25, discovering cell-type-specific translation of 3,857 alternative transcripts across 1,641 genes and identifying isoforms of the same genes undergoing differential translation within and across 8 different cell types.
We defined high and low translational states in CA1 and CA3 neurons, with synaptic and metabolic genes enriched in high states.
We found that CA3 exhibited higher basal translation compared with CA1, as confirmed by metabolic labelling of newly synthesized proteins and immunohistochemistry of translational machinery components.
This accessible platform will expand our understanding of how cell-type-specific and isoform-specific translation drives brain physiology and disease.
