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Previously unknown method of neurotransmission identified.

The neuronal gene Arc is essential for long-lasting information storage in the brain, mediating various forms of synaptic plasticity and is implicated in neurodevelopmental disorders. However, little is known about Arc’s molecular function and evolutionary origins.  Now, two independent studies from researchers at the University of Utah and the University of Massachusetts Medical School shows Arc can send its genetic material from one neuron to another by employing a strategy commonly used by viruses. The teams state their studies unveil a previously unknown way nervous system cells interact and perform neurotransmission.  The studies are both published in the journal Cell.

Previously studies have shown while the Arc protein is known to play a vital role in the brain’s ability to store new information, little is known about how it works. In addition, studies have shown detailed similarities between the Arc protein and proteins found in certain viruses like HIV, however, it was unclear how those commonalities influenced the behavior of the Arc protein.  The current studies identify an entirely new process by which neurons send genetic information to one another.

The current study from the University of Utah examines the Arc gene by introducing it into bacterial cells.  Results show when bacterial cells make the Arc protein, it clumps together into a form resembling a viral capsid, the shell that contains a virus’ genetic information. Data findings show the Arc proteins appear to mirror viral capsids in their physical structure as well as their behavior and other properties.

The current study from the University of Massachusetts utilizes fruit flies to investigate the contents of tiny sacks released by cells called extracellular vesicles. Results show motor neurons controlling the flies’ muscles release vesicles containing a high concentration of the Arc gene’s messenger RNA (mRNA), the DNA-like intermediary molecule cells use to create the protein encoded by a DNA sequence. Both studies also found evidence the Arc capsids contain Arc mRNA, with it suggesting the capsids are released from neurons inside those vesicles. In addition, the University of Utah study shows the more active the neurons are, the more of those vesicles they release.

Further experiments performed by both groups suggest Arc capsids act like viruses by delivering mRNA to nearby cells. The University of Utah researchers grew mouse neurons lacking the Arc gene in Petri dishes filled with Arc-containing vesicles and Arc capsids. Results show the formerly Arc-less neurons took in the vesicles and capsids and used the Arc mRNA contained within to produce the Arc protein themselves. Data findings show just like neurons known to naturally manufacture the Arc protein when the cells made more of the protein their electrical activity increased.

The UMass researchers, meanwhile, show Arc mRNA and capsids travel only in a single direction between fly cells, namely from motor neurons to muscles, with the Arc protein binding to a specific part of the Arc mRNA molecule called the untranslated region not used to make the Arc protein. The team also observed flies lacking the Arc gene form fewer connections between their motor neurons, and while normal flies create more of these connections when their motor neurons are more active, flies without the Arc gene failed to do so.

The teams surmise their studies identify a trans-synaptic mRNA transport mechanism involving retrovirus-like capsids and extracellular vesicles, a new mode of neurotransmission.  For the future, the researchers state they now plan to investigate why cells use this virus-like strategy to shuttle Arc mRNA between cells and whether this system might allow the toxic proteins responsible for Alzheimer’s disease to spread through the brain.

Source: National Institutes of Health (NIH)

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