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August 9, 2017

Single Protein Keeps Mouse Brains Youthful

Overexpressing a single gene called Arc rejuvenates the visual cortex of middle-aged mice, making them as plastic as younger mice. [Elissa Pastuzyn/University of Utah]

  • As we get older, our brains lose plasticity—essentially the ability to adapt to stimuli and experiences.  In the visual cortex, for example, brain plasticity appears to be maintained during a "critical window" of time during early childhood, and once this window has closed it doesn’t normally reopen. This explains why some conditions, such as lazy eye, can be corrected in young children, but not when we get older.

    Studies by scientists at the University of Utah Health and the Massachusetts Institute of Technology (MIT) now suggest that increasing the expression of a single gene know as Arc in the visual cortex of older mice effectively reopens that window of plasticity. Although the studies were carried out in animal models, it isn’t unreasonable to project that if the same mechanisms are at work in human brains, then boosting levels of Arc could feasibly help to prevent the natural course of cognitive decline as we get older or even aid the brain’s recovery from injury, suggests Jason Shepherd, Ph.D., associate professor of neurobiology and anatomy at University of Utah Health.

    “The brain's job is to process information from the outside world and it adapts to experience and the environment it's exposed to,” Dr. Shepherd explained to GEN. “The visual cortex can adapt to changes in visual experience so that it can better process visual information. This ‘plasticity’ is mostly evident early on in development during critical windows.”

    Previous work by Dr. Shepherd and Mark Bear, Ph.D., at MIT, had demonstrated that Arc was essential for experience-dependent synaptic plasticity in the visual cortex. Essentially, the visual cortex of young mice that lacked Arc didn’t respond to the closure of one eye (monocular deprivation) for a few days in the same way as the visual cortex of normal young mice. In animals with normal Arc levels, temporary monocular deprivation results in synapses weakening and being eliminated, which leads to the loss of vision in that eye, a condition known as amblyopia, Dr. Bear explained to GEN.  But amblyopia from monocular deprivation only happens in young animals during the early postnatal period, the so-called "critical period." “Monocular deprivation later in life fails to depress synapses in the visual cortex.”

    Independent studies have separately suggested that an overall reduction in cortical activity as we age—due in part to increased inhibition—is responsible for the loss of juvenile plasticity, Dr. Bear noted. “But it has remained unclear how this change in activity could alter the properties of synaptic plasticity. Jason and I realized that changes in Arc protein might provide a simple unifying explanation.”

    In fact, Arc's role in synaptic plasticity in other brain regions, especially in the hippocampus, is well documented, Dr. Shepherd continued. “Since it seemed like Arc played such an important role in cortical plasticity, we hypothesized that its expression was important for controlling the critical period.”

    The team’s latest studies in normal mice first confirmed that in the mouse visual cortex, levels of Arc rise to match peak visual plasticity in "teenaged" animals, and then drop significantly during "middle age." This indicated that Arc levels and plasticity were linked. The researchers then turned to a mouse model created by collaborators Hiroyuki Okuno, Ph.D., and Haruhiko Bito, M.D., Ph.D., at the University of Tokyo, in which Arc is overproduced in adult mice. The University of Utah and MIT collaborators found that these animals responded to monocular deprivation later in life with the same level of synaptic depression as that of younger animals. Permanently elevated Arc levels in these animals’ visual cortex had kept that window of plasticity open into adulthood.

    In a second set of experiments, the team used a viral vector to deliver the gene for Arc into the visual cortex of adult mice in which the critical window had already closed. These animals also responded to visual deprivation in the same way as young animals, indicating that boosting Arc levels was sufficient to reopen that window of plasticity.

    Drs. Shepherd, Bear, and colleagues reported on their studies yesterday in the early online edition of Proceedings of the National Academy of Sciences, in a paper entitled “Arc Restores Juvenile Plasticity in Adult Mouse Visual Cortex.”

    The researchers are currently looking at how Arc impacts on other areas of the mouse brain. “ … since Arc's role in synaptic plasticity seems to be conserved across brain regions, we think it is likely that fine tuning Arc levels in adult/aged brains will improve synaptic plasticity in those regions,” Dr. Shepherd suggested to GEN. “However, we don't yet know if these regions show a decline in the induction of Arc as dramatically as in the visual cortex during aging.”

    It’s also not known whether results in mice can be extrapolated to humans, although the concept that parallel mechanisms exist isn’t unreasonable, he indicated. “We do not know whether the same processes are used during human brain development, but we think it's very likely. Arc is very conserved from mouse to human. But human brain development is a much longer process with multiple developmental stages. Most critical windows of human brain plasticity end around 10–12 years of age, just before adolescence.”

    There is also existing evidence that the human visual cortex does have a window of plasticity, Dr. Shepherd added. Adults who have had childhood cataracts may continue to have vision problems later in life. “Even though these cataracts can be restored, so that the retina is working properly, the brain cannot process information coming in from the retina because it's not plastic enough as an adult. This is similar to what we modeled in mice. If we extrapolated to humans, we would predict that boosting Arc levels in adults with cortical blindness could lead to restoration or improvement in vision.”

    Independent studies have also implicated low levels of Arc, in addition to other synaptic proteins, during aging and dementia, and Dr. Shepherd’s laboratory aims to determine more definitively if Arc levels are associated with normal cognitive aging in brain structures such as the hippocampus, which mediates memory.

    Even if Arc is found to represent a promising target for therapeutic intervention, it may not itself be inherently druggable, Dr. Shepherd stressed. “While Arc seems to be an attractive target for therapeutics, it's not an easy target for pharmacology. My lab aims to understand how it mediates synaptic plasticity at the molecular level, which may provide easier pharmacological targets.”

    There is a great deal of work yet to be carried out in animal, but looking to the future, the potential uses of Arc in a therapeutic context are manifold, he concluded. “If we could find a specific way of boosting Arc levels, we could potentially use this to boost brain plasticity in many contexts. These include recovery from traumatic brain injury and stroke. It could also be used to prevent normal cognitive decline that's associated with aging, independent of dementias.”

     

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