RNA transmission between brain cells

A colorful depiction of a virus, some of which contain genes that resemble the unusual Arc genes in neurons. Copyright CC0 1.0 Universal.

Cells in the brain (called neurons) communicate with each other by passing electrical and chemical signals to one another. In doing so, groups of neurons form circuits which serve as the foundation for your entire mental life, including all of your thoughts, memories, and experiences! A neuron is generally thought to ‘speak’ with other neurons by releasing proteins, called neurotransmitters, that induce a dramatic change in the recipient’s electrical properties. In addition, some neurons can influence their partner’s electrical properties directly, through gap junctions, without the use of a protein intermediate. In a new and exciting paper, Dr. Jason Shepherd’s lab at the University of Utah found that neurons can also communicate with one another by sharing transcriptomic material (RNA), in addition to the aforementioned means of electrical dialogue. Dr. Shepherd and his team found that a specific RNA transcript, which has previously been shown to facilitate things like learning, memory, and brain plasticity, can be shared between neurons, presumably as a means of communicating meaningful changes in the experience of the animal. Incredibly, Shepherd’s lab was able to convincingly show that this RNA-transmission is facilitated by an evolutionary hijacking of a basic mechanism by which viruses are able to replicate and transmit their DNA to host organisms. These new results underscore how little we actually know about the mechanisms of the brain, and propose a completely new means by which the atomic units of the brain, neurons, can share information in order to adapt to new experiences.

The Arc gene, present in most higher vertebrates (like you!), has been very puzzling and intriguing to scientists for nearly 35 years. It falls into a class of genes known as Immediate Early Genes (IEGs), which are highly expressed after meaningful neuronal activity. Basically, when a neuron is strongly activated (for example, after a memorable experience), it often needs new machinery in order to change and strengthen certain synapses. This machinery usually comes in the form of many genes being expressed to produce new proteins that can shape the way the cell functions in the brain. IEGs are the first wave of new genes that are produced in order to facilitate these neuronal changes (plasticity). IEGs come in diverse forms, from transcription factors that can regulate many other genes, to proteins that actually impact individual synapses between neurons. The actual function and role of the IEG Arc has remained a mystery, until now!

Previous studies of the Arc gene, however, were able to show that it possesses some very unusual features. Most importantly, scientists in the 80s and 90s showed that the Arc gene is selectively expressed when a neuron has particularly strong levels of activity, and that the transcripts of the gene are actually trafficked to the synapse which activated that neuron! Somehow, the Arc mRNA is able to find its way to synapses that were recently active, providing an exciting means of local, synaptic support and strengthening. In fact, this feature of the gene was so important that genetically-engineered mice lacking Arc were unable to store experiences into long-term memory. One other important piece of the puzzle that was previously shown was that the Arc gene shows remarkable homology to another, very distant, set of genes: those found in viruses!

Viruses are self-replicating genomic ‘drifters’ that package their genetic material into a little cocoon (known as the viral capsid) and spread from host cell to host cell, inserting their genetic material into the genomes of the cells they infiltrate. If viruses can insert their DNA into our DNA, wouldn’t our DNA be completely bogged down with artifactual viral genomic sequences that were inserted into our ancestors’ DNA?

This is, in fact, the case! A large portion of the human genome is composed of these leftover viral sequences: since these large swaths of our genome don’t actually encode any useful proteins, they are often described as ‘junk DNA’. However, evolution is a crafty sculptor and makes do with what it has! At some pivotal point in our species’ history, a piece of viral DNA encoding the capsid (called the Gag gene) was inserted into our mammalian DNA. Then, through a series of random mutations and processes, this gene became extremely useful to neurons. It turns out, this repurposed viral gene is Arc! But what could this strange and ancestral viral-packaging protein have to do with brain function?

Dr. Shepherd provides a good answer to this question in the aforementioned paper. Their paper shows that the Arc protein actually forms a capsid-like structure, which packages the original Arc mRNA into itself. How meta! After packaging this mRNA into the capsid, neurons release it into their local environment, where it can be absorbed by other neurons. Once transferred, the recipient neurons can then translate the Arc transcripts into more capsid-like protein structures, and the cycle can repeat again. This fundamental discovery shows that during periods of strong neuronal activity, like learning, neurons can communicate with each other by actually trafficking mRNA between each other. This breakthrough shifts the way we look at how brains function, and rewrites the dogma that neurons communicate via directional electrochemical means. Furthermore, because Arc is thought to signal plasticity of plasticity (metaplasticity) and engage in processes like learning and memory, this discovery proposes new mechanisms for how groups of neurons can change in targeted ways to form functional circuits in the brain.

Many questions still remain before the story of the Arc gene is finished. Are there other RNA transcripts being shared by the Arc-capsids? How does the viral-capsid method of DNA delivery change our understanding of how the brain can adapt to new experiences? Furthermore, how does this finding change our views on the source of the synaptically-targeted mRNA transcripts, mentioned earlier in this review? These are questions that will be asked by many labs, all over the world, in response to this study. So, if you are curious about these questions and the function if Arc in general, stay tuned!

Edited by Kristin Muench

References:

Pastuzyn, Elissa D., et al. "The neuronal gene Arc encodes a repurposed retrotransposon Gag protein that mediates intercellular RNA transfer." Cell 172.1-2 (2018): 275-288.