Abstract
Neurobiological studies of aging are beginning to link functional changes with a loss of experience-dependent plasticity. In the visual system, age-related functional changes include decreases in visual acuity, orientation selectivity, motion perception, and ocular dominance plasticity. A recent paper has shown that Ube3A, an E3 ubiquitin ligase that is absent in Angelman's syndrome, is required for experience-dependent plasticity during development of the visual cortex. Knocking out Ube3A during development leads to rigidity of ocular dominance plasticity that is strikingly similar to the reduced plasticity seen in older animals. Furthermore, ubiquitin ligases have been linked with age-related neurodegenerative disorders and longevity. Ubiquitin ligases selectively mark proteins for degradation, and a balance between synaptic proteins and their degradation is important for neural transmission and plasticity. This led us to ask whether normal aging is characterized by a loss of Ube3A in the cortex. We used Western blot analysis in order to quantify Ube3A expression across the life span of humans, macaque monkeys, and cats. We found that Ube3A expression declines across the lifespan in human, monkey, and cat cortex. The losses were substantial (50–80%) in all areas studied which includes V1, V3, V4, frontal, and auditory cortex. In addition, when compared with other synaptic proteins there was a selective loss of Ube3A in human cortex. The progressive loss of Ube3A expression during cortical aging is an important new finding. Furthermore, the selective loss of Ube3A in human cortex highlights a specific vulnerability in human brain aging that may signify a dramatic shift in cortical function and plasticity.
Highlights
A common way of describing the behavior of older adults is that they are more rigid and set in their ways
We took samples from different regions of V1, to examine whether Ube3A might play a role in the loss of peripheral vision that occurs in normal aging (Sekuler et al, 2000)
Our study found that Ube3A expression declines across the lifespan in human, monkey, and cat cortex
Summary
A common way of describing the behavior of older adults is that they are more rigid and set in their ways. The wide range in sensory and cognitive functional changes that accompany normal, healthy aging are suggestive of widespread cortical dysfunction. Neurobiological studies are beginning to link these functional changes and common descriptions with a loss of experiencedependent plasticity that reflects age-related changes in synaptic plasticity mechanisms (Burke and Barnes, 2006). The common explanation for these changes is a loss of GABA-mediated inhibition in the aging visual cortex because application of GABA to visual cortical neurons reinstates normal receptive field tuning properties (Leventhal et al, 2003). Recent studies have highlighted the important role of ubiquitin-mediated degradation of proteins at the synapse as a potent mechanism for changing synaptic structure and function (DiAntonio and Hicke, 2004), and the loss of ubiquitin ligases in neurodegeneration (Ardley and Robinson, 2004). Little has been known about changes in the expression of ubiquitination machinery in human cortex across the lifespan into normal, healthy aging
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