Joshua Sanes (l) and Melanie Samuel
Neurons form precise relationships with particular synaptic partners and these relationships give rise to the wiring diagram that enables cognitive function. Like other partnerships, neural connections need to be maintained over the course of a lifetime to ensure proper function. But time is not kind to the brain. As we age, neural function can become compromised, even in otherwise healthy adults, resulting in mobility defects, cognitive decline, and memory deterioration. These functional deficits suggest that neural integrity pathways may be compromised by old age, but little is known about which partnerships are prone to failure or what molecules are responsible. A major impediment to deciphering the critical cellular and molecular steps leading to age-related cognitive decline is that most documented age-related alterations in synaptic structure, function, and number are subtle and difficult to appreciate in the dense neuropil of the brain. To circumvent this problem, Samuel and colleagues focused on synapses in the outer retina, which are particularly large. In this region, photoreceptors, which sense light, synapse on interneurons, which process the signals before sending them deeper into the brain. Importantly, there was already evidence that these synaptic relationships are particularly tenuous as they dramatically remodel in old rodents and humans. The outer retina is therefore well-suited to the search for molecular events that underlie age-related synaptic decline. In their paper in Nature Neuroscience, Samuel et al. find that one of the culprits is an energy homeostatic pathway regulated by the kinase LKB1 and one of its targets AMPK.
Samuel et al. show that deleting either LKB1 or AMPK makes young neurons appear old; cells and synapses remodel identically to old counterparts and their function declines. Correspondingly, defects in these molecules accompany normal aging, as the levels of LKB1 and activation of AMPK both decrease in old age. This pathway appears to be specific, as aging spares other LKB1 targets, and retinas from associated mutants are normal. Do neural aging defects arise from LKB-induced alterations in both synaptic partners or in one in particular? To assess this possibility, Samuel et al. deleted LKB1 from only one cell type, the rod photoreceptors. Rod-only LKB1 deletion was sufficient to induce the range of aging defects observed in total retina knockouts, placing these cells at the center of the outer retina’s relationship problem. Indeed, in follow-up studies, Samuel et al. reconstructed individual neurons to show that rod axon retraction drives age-related synaptic remodeling.
These data raise the possibility that modifying the LKB1-AMPK axis could prevent or mitigate neural misorganization in old age. To address this, Samuel et al. increased AMPK activity using a genetic method and found this helped prevent neural partnerships from deteriorating and improved connections that had already begun to degrade. They then went on to use pharmacologic agents and caloric restriction, both of which affect this pathway. Again, normal age-related changes were at least partially suppressed. These data support the idea that particular molecular programs maintain neural function in old age and provide hope that by targeting these pathways we may improve the longevity of neural partnerships.