Changes in Synaptic Ultrastructure Connected to Age-Related Impairment of Working Memory

In today's open access paper, researchers report the discovery of differences in the synaptic ultrastructure of aging primates, differences that are connected to loss of memory function. The working hypothesis is that faltering mitochondrial activity inhibits correct formation of synapses, and that this issue is one of the important factors to distinguish individuals that go on to develop worse memory performance in later life.

Every cell contains hundreds of mitochondria, descendants of ancient symbiotic bacteria. Mitochondria are responsible for generating the chemical energy store molecules, adenosine triphosphate, that power cellular processes. It is well known that this activity declines with age, perhaps largely due to failing quality control of damaged mitochondria. Autophagy targeted to mitochondria, known as mitophagy, recycles worn and damaged mitochondria, but is shown to become less effective with age. This occurs for a variety of proximate causes that include changes to mitochondria themselves, as well as failures in parts of the complex autophagy mechanisms.

In energy-hungry tissues like the brain and muscles, loss of mitochondrial activity likely produces a sizable contribution to age-related dysfunction. Many different cellular processes will be affected, and the example in today's paper is but one of these. Restoration of mitochondrial function in older individuals is an important goal for the research community, but so far the range of available interventions have struggled to outperform the effects of exercise and calorie restriction. This includes mTOR inhibition, mitochondrially targeted antioxidants, NAD+ precursor supplements, and so forth. One might hope that the next generation of interventions, including transplantation of functional mitochondria, will produce more impressive outcomes.

Mitochondria power-supply failure may cause age-related cognitive impairment

Brains are like puzzles, requiring many nested and codependent pieces to function well. The brain is divided into areas, each containing many millions of neurons connected across thousands of synapses. These synapses, which enable communication between neurons, depend on even smaller structures: message-sending boutons (swollen bulbs at the branch-like tips of neurons), message-receiving dendrites (complementary branch-like structures for receiving bouton messages), and power-generating mitochondria. To create a cohesive brain, all these pieces must be accounted for.

Prior studies had found that brains lose synapses as they age, and the researchers saw this pattern in their non-human primate model, too. But when they looked at the synapses that remained, they found evidence of a breakdown in coordination between the size of boutons and the mitochondria they contained. A fundamental neuroscientific principle, the ultrastructural size principle, explains that whenever one part of the synaptic complex changes in size, so too must all the other parts. The synapse, the mitochondria, the boutons - all these parts must scale in accordance with one another. The team found that adherence to the ultrastructural size principle was essential for avoiding working memory impairment with age. By viewing violation of the ultrastructural size principle and mitochondria-related failures as the key to age-related cognitive impairment, the study ushers in a new era for aging research.

Violation of the ultrastructural size principle in the dorsolateral prefrontal cortex underlies working memory impairment in the aged common marmoset (Callithrix jacchus)

Here, we tested the hypothesis that changes to synaptic ultrastructure that affect synaptic efficacy stratify marmosets that age with cognitive impairment from those that age without cognitive impairment. We utilized electron microscopy to visualize synapses in the marmoset dorsolateral prefrontal cortex (dlPFC) and measured the sizes of boutons, presynaptic mitochondria, and synapses. We found that coordinated scaling of the sizes of synapses and mitochondria with their associated boutons is essential for intact working memory performance in aged marmosets. Further, lack of synaptic scaling, due to a remarkable failure of synaptic mitochondria to scale with presynaptic boutons, selectively underlies age-related working memory impairment.

We posit that this decoupling results in mismatched energy supply and demand, leading to impaired synaptic transmission. We also found that aged marmosets have fewer synapses in dlPFC than young, though the severity of synapse loss did not predict whether aging occurred with or without cognitive impairment. This work identifies a novel mechanism of synapse dysfunction that stratifies marmosets that age with cognitive impairment from those that age without cognitive impairment. The process by which synaptic scaling is regulated is yet unknown and warrants future investigation.