QnAs with Erin Schuman

Neuroscientist Erin Schuman says her career goal is to understand exactly how single neurons work. Specifically, she wants to know how neurons keep the right proteins at the right concentration in the right place at the right time to function properly in the brain. Schuman is perhaps best known for her role in discovering that neurons can synthesize proteins outside the cell body and within dendrites, a phenomenon called local protein synthesis. Her Inaugural Article (1) expands on that finding by exploring how messenger RNA (mRNA) molecules move in real time around synapses and get translated into proteins. Schuman and her husband, neuroscientist Gilles Laurent, are cofounders and directors of the Max Planck Institute for Brain Research in Frankfurt, Germany. Schuman was elected to the National Academy of Sciences in 2020 and discussed her most recent work with PNAS.

Erin Schuman. Image credit: Camille Laurent (Frankfurt International School, Oberursel, Germany).

PNAS: What was the impact of the discovery of local protein synthesis within dendrites on neuroscience?

Schuman: Most of a neuron’s real estate is outside the cell body, in the dendrites and the axons. But people hadn’t thought much about how that huge space could be served in terms of proteins. Most assumed proteins were made in the cell body and transported where they needed to go. There are around 10,000 synapses in a neuron and probably 1,000 different proteins at every synapse. If the cell body was a post office, it would have to service 10,000 postboxes with 1,000 different people getting mail at each postbox. Some early structural studies made the provocative suggestion that proteins may be produced at synapses. But the idea didn’t get much traction until we bumbled into the field with an experiment looking at synaptic plasticity caused by a growth factor (2, 3). We found that to exhibit plasticity the synapse needed the protein immediately, suggesting it must be coming from a local source. When we cut away the cell bodies and recorded directly at the synapse, we showed that the source of the protein was local. People thought it was [far-fetched], but right away others started coming to the same conclusion in their systems. Even so, it’s been an uphill battle.

PNAS: Along with major discoveries, you are known for developing techniques for studying neurons, plasticity, and synapses. Is your Inaugural Article (1) focused on technique development or experiments?

Schuman: It’s a combination. We apply and optimize tools to study mRNAs moving in cells and to study protein synthesis of endogenous proteins. My colleague, Paul Donlin-Asp, together with Alexander Heckel and Robin Klimek, developed molecular beacons that find the mRNAs of interest and light them up so we can see them moving around inside the neuron, showing us where the mRNA is going. He also used a CRISPR system to edit endogenous genes and make their corresponding proteins fluorescent. The study sets a high bar for the kind of resolution you can have, showing you can look at individual molecules near synapses and in dendrites and watch them move and pause in real time.

PNAS: What did you find?

Schuman: Proteins are synthesized in the dendrites, but before a protein can be made an mRNA needs to be there. If you look in fixed cells you can see thousands of mRNAs stuck in different positions in the dendrite, but you don’t get any sense of the dynamics. Our beacons allow us to watch mRNA movements in living cells. To try to understand if there are general principles for mRNAs, we looked at three important synaptic mRNAs. We got very refined measurements that allowed us to understand how things work in a way that we could not intuit from static images. We see that the mRNA molecules are basically scanning, moving up and down in the dendrite. They stop and hover in a place and then move to another place, and then they move back.

We also asked what happens to the system when you induce plasticity by either potentiating synapses or depressing synapses. We wanted to know if just having an mRNA at a synapse was sufficient to drive protein synthesis. The second half of the paper looked directly at the synthesis of these proteins using two different methods. We found that all three mRNAs are much more likely to dwell at synapses with plasticity, but they didn’t behave the same way in terms of their translation. Two of them had increased translation; the other didn’t. We think we’ve now successfully uncoupled these two processes. The delivery and localization of the mRNA is regulated by plasticity. The translation of the mRNA is a second, independent step. We imagine that the recruitment of the mRNAs is a more general step and translation is more specific.

PNAS: What are the implications of these findings?

Schuman: This work shows the kind of control and flexibility built into dendrites and synapses. Depending on what recently happened—what kind of modulation a synapse saw or the pattern of activity it received—a synapse can pick and choose how it wants to modify itself. It can stimulate the translation of one mRNA and not another. It can also increase or decrease the level of translation of mRNAs. This imparts flexibility and specificity to the system because it means that each individual synapse can selectively choose the proteins that it needs to modify itself more or less.

On a broader level, this field is in the spotlight because many of the molecules whose mRNAs are present in dendrites are on the hit list for neurodevelopmental disorders like autism spectrum disorder, including fragile X syndrome. This uncoupling of mRNA delivery and the synthesis of proteins tells researchers in those areas to look at these things as distinct. For us, the next phase is to measure protein synthesis in vivo [by] putting fluorescent reporters into living animals.