Brains are like puzzles, requiring many nested and codependent pieces to operate well. The brain is split into areas, each containing many tens of millions of neurons connected across 1000’s of synapses. These synapses, which enable communication between neurons, rely on even smaller structures: message-sending boutons (swollen bulbs on the branch-like suggestions 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 have to be accounted for.

Nonetheless, within the aging brain, these pieces can wander off or altered and not fit within the greater brain puzzle.

“Fifty percent of individuals experience lack of working memory with old age, meaning their ability to carry and manipulate information within the short-term decreases,” says co-first writer Courtney Glavis-Bloom, a senior staff scientist in Salk Institute Professor John Reynolds’ lab. “We set out to know why some individuals maintain healthy working memory as they age, while others don’t. In the method, we discovered a novel mechanism for the synaptic basis of cognitive impairment.”

Prior studies had found that brains lose synapses as they age, and the researchers saw this pattern of their non-human primate model, too. But after they checked out the synapses that remained, they found evidence of a breakdown in coordination between the scale of boutons and the mitochondria they contained. A fundamental neuroscientific principle, the ultrastructural size principle, explains that every time one a part of the synaptic complex changes in size, so too must all the opposite parts. The synapse, the mitochondria, the boutons-;all these parts must scale in accordance with each other. Before the Salk team’s study, published in Frontiers in Aging Neuroscience on April 12, 2023, no one had asked whether this principle might be violated with age or disease.

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

“It’s a ripple effect, with unfathomably small synaptic structures altering networks of neurons, brain function, and behavior,” says Glavis-Bloom. “Investigating these microscopic dysfunctions is uncharted territory that would revolutionize our understanding of aging and its impact on cognition.”

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 important thing to age-related cognitive impairment, the study ushers in a latest era for aging research.

The photographs we now have captured of synapses are snapshots of a dynamic process. With these snapshots in hand, we are able to begin to think first in regards to the mechanisms that coordinate the expansion and contraction of the assorted parts of the synaptic complex, then ask how disruption of those mechanisms can explain age-related cognitive decline. This opens a wholly latest way of desirous about cognitive decline that could lead on to latest targets for future therapeutics.”

John Reynolds, Salk Institute Professor, Holder of the Fiona and Sanjay Jha Chair in Neuroscience

Other authors include Sammy Weiser Novak and Uri Manor of the Salk Institute; and Masaaki Kuwajima, Lyndsey Kirk, and Kristen M. Harris of the University of Texas at Austin.

Source:

Journal reference:

Glavis-Bloom, C., et al. (2023) Violation of the ultrastructural size principle within the dorsolateral prefrontal cortex underlies working memory impairment within the aged common marmoset (Callithrix jacchus). Frontiers in Aging Neuroscience. doi.org/10.3389/fnagi.2023.1146245.