Viral communication between neurons during memory formation
Writer: Alexandra Gilbert
Editor: Karolay Lorenty
Artist: Lucie Gourmet
As viruses have done since the dawn of evolutionary time 1.5 billion years ago, they cajole the host cell’s machinery into manufacturing viral proteins. The efficiency of this strategy makes for lethal, incurable illnesses, but also for essential functions in the body. On an evolutionarily ancient timescale, encounters with viruses have led to their incorporation into our genome. So much so that endogenous viral mechanisms are essential for forming and maintaining long-term memory. How is this possible?
The immediate early gene Arc, found exclusively in neurons, was recently found to have the characteristic features of a retrovirus. Most importantly, it plays an essential role in memory.
The transmission of Arc genes is bizarre and challenges traditional views of long-term memory formation and maintenance. During synaptic plasticity, neurons dynamically change the nature of their connections: their shape, their receptivity to other neurons, and their internal environment. For instance, receptors are inserted into the synaptic membrane so that the neuron becomes more sensitive to incoming signals and is more likely to fire when exposed to a new stimulus.
Interestingly, the way Arc genes regulate memory and synaptic plasticity is similarly activity-dependent. After transfection of the Arc capsid into neighbouring “host” neurons, the genes lie dormant, concentrated at the dendrite. When the neuron is activated, its genetic machinery transcribes the Arc gene into proteins that aid in the trafficking of receptors to the synaptic membrane. Once transcribed, Arc proteins maintain this newly formed synaptic strength, not only allowing for memory consolidation and reconsolidation in hippocampal neurons but also plasticity in the visual cortex. The result is that we are able to adapt to new visual stimuli.
When Arc is knocked out, mice show signs of diminished ability to adapt to new stimuli and form new memories, reiterating the integral function that this virally-derived regulatory gene serves in memory consolidation. Scientists have also examined the effects of enhanced Arc function. In the visual cortex, overexpressed Arc increases the capabilities of adult mice to learn new visual stimuli to the same level as young, developing mice.
The growing interest in Arc genes doesn’t only feature advances in our understanding of memory. Scientists propose that Arc’s unique trafficking mechanisms could be used in a variety of applications, such as viral vectors, which are commonly used in synaptic imaging research and in delivering gene therapy to neurons of choice. Generally, viral vectors are composed of the Rabies virus, but its use in the delivery of fluorescent labels or gene therapies can trigger immune responses. Since Arc genes are endogenous, they provide a safer alternative to traditional viruses. Additionally, reports arise describing the ability of Arc capsids to encapsulate not only their own RNA, but other genes and proteins, which opens doors to gene therapies targeting other molecular players within the synapse.
Is the virus-like Arc gene pushing the frontiers of gene therapy and treatment for cognitive impairment? The gene holds beneficial functional significance, at least preliminarily. Future research will reveal just how significant this ancient vehicle may be.
References
Budnik, V., & Thomson, T. (2020). Structure of an Arc-ane virus-like capsid. Nature Neuroscience, 23(2), 153-154. doi: 10.1038/s41593-019-0580-3
Erlendsson, S., Morado, D., Cullen, H., Feschotte, C., Shepherd, J., & Briggs, J. (2020). Structures of virus-like capsids formed by the Drosophila neuronal Arc proteins. Nature Neuroscience, 23(2), 172-175. doi: 10.1038/s41593-019-0569-y
Day, C., & Shepherd, J. (2015). Arc: building a bridge from viruses to memory. Biochemical Journal, 469(1), e1-e3. doi: 10.1042/bj20150487
Jenks, K., Kim, T., Pastuzyn, E., Okuno, H., Taibi, A., & Bito, H. et al. (2017). Arc restores juvenile plasticity in adult mouse visual cortex. Proceedings Of The National Academy Of Sciences, 114(34), 9182-9187. doi: 10.1073/pnas.1700866114
Kedrov, A., Durymanov, M., & Anokhin, K. (2019). The Arc gene: Retroviral heritage in cognitive functions. Neuroscience & Biobehavioral Reviews, 99, 275-281. doi: 10.1016/j.neubiorev.2019.02.006
McCurry, C., Shepherd, J., Tropea, D., Wang, K., Bear, M., & Sur, M. (2010). Loss of Arc renders the visual cortex impervious to the effects of sensory experience or deprivation. Nature Neuroscience, 13(4), 450-457. doi: 10.1038/nn.2508
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