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Electron micrographs of neurons in the brain showing presynaptic boutons (yellow), mitochondria (purple), and synapses (blue). Credit: Salik Institute

Minds are like puzzles, requiring many interlocking and dependent pieces to work well. The brain is divided into regions, each containing several million neurons connected via thousands of synapses. These synapses, which enable communication between neurons, depend on smaller structures: message-transmitting dendrites (bulging bulbs at the terminals of branch-like neurons), message-receiving dendrites (the complementary branch-like structures for receiving bouton messages), and force-generating mitochondria. To create a cohesive brain, all of these pieces must be accounted for.

However, in an aging brain, these pieces can get lost or shifted, and no longer fit into the larger brain puzzle. A research team has now published a study in Frontiers in aging neuroscience about this subject.

“Fifty percent of people experience a loss of working memory with age, which means their ability to retain and process information in the short term,” says co-author Courtney Glavis Blum, senior scientist at the Salk Institute Professor John Reynolds. laboratory. “We set out to understand why some individuals retain a healthy working memory as they age, while others do not. In the process, we discovered a new mechanism for the synaptic basis of cognitive impairment.”

Previous studies have found that brains lose synapses with age, and the researchers saw this pattern in a non-human primate model as well. But when they looked at the remaining synapses, they found evidence of a breakdown in coordination between the size of the granules and the mitochondria that contained them.

A basic neuroscience principle, the ultrastructural size principle, explains that when one part of the synaptic complex changes in size, all the other parts must also change. The synapse, the mitochondria, the rods – all these parts must fit in accordance with each other. Prior to the Salk team’s study, no one had asked whether this principle could be violated with age or disease.

“To examine this, we turned to electron microscopy,” says co-first author Casey Vanderlip, a former research assistant in Reynolds’ lab. “This enabled us to visualize these components across many synapses. We found that synaptic loss occurred with healthy and frail aging, but what differed was a breakdown in the relationship between the sizes of boutons and their mitochondria.”

“It’s a ripple effect, with small, unfathomable synaptic structures that alter neuronal networks, brain function, and behavior,” Glavis Blum says. “Investigating these microscopic imbalances is uncharted territory that could revolutionize our understanding of aging and its impact on cognition.”

Normally, the different parts of the synaptic complex grow and contract together. The researchers found evidence that this process can deviate with age and that this may contribute to cognitive impairment. Credit: Salik Institute

The team found that adhering to the infrastructure size principle was necessary to avoid working memory impairment with age. By looking at violation of the ultrastructural size principle and associated mitochondrial failure as a key to age-related cognitive impairment, the study heralds a new era for aging research.

“The images we’ve taken of synapses are snapshots of a dynamic process,” says Reynolds, Fiona and Sanjay Jha Chair Holder in Neuroscience. “With these snapshots in hand, we can begin to consider first the mechanisms that coordinate the expansion and contraction of different parts of the synaptic complex, and then ask how disruption of these mechanisms might explain age-related cognitive decline. This opens up a completely new way of thinking about cognitive decline that can lead to new targets for future therapies.”

Other authors include Sammy Weiser-Novak and Uri Manor of the Salk Institute. and Masaaki Kawajima, Lindsey Kirk, and Christine M. Harris of the University of Texas at Austin.

more information:
Violation of the ultrastructural size principle in the dorsolateral prefrontal cortex underlies working memory impairment in the elderly common monkey (Callithrix jacchus), Frontiers in aging neuroscience (2023). DOI: 10.3389/fnagi.2023.1146245

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