Document Type
Article
Publication Date
2-1-2024
Original Citation
Heuer S,
Nickerson E,
Howell G,
Bloss E.
Genetic context drives age-related disparities in synaptic maintenance and structure across cortical and hippocampal neuronal circuits. Aging Cell. 2024;23(2):e14033
Keywords
JMG, SS1, Humans, Mice, Animals, Aged, Mice, Inbred C57BL, Hippocampus, Neurons, Pyramidal Cells, Synapses, Neuronal Plasticity
JAX Source
Aging Cell. 2024;23(2):e14033
ISSN
1474-9726
PMID
38130024
DOI
https://doi.org/10.1111/acel.14033
Grant
National Institute on Aging, Grant/Award Number: AG055104, AG062409 and AG079877
Abstract
The disconnection of neuronal circuitry through synaptic loss is presumed to be a major driver of age-related cognitive decline. Age-related cognitive decline is heterogeneous, yet whether genetic mechanisms differentiate successful from unsuccessful cognitive decline through maintenance or vulnerability of synaptic connections remains unknown. Previous work using rodent and primate models leveraged various techniques to imply that age-related synaptic loss is widespread on pyramidal cells in prefrontal cortex (PFC) circuits but absent on those in area CA1 of the hippocampus. Here, we examined the effect of aging on synapses on projection neurons forming a hippocampal-cortico-thalamic circuit important for spatial working memory tasks from two genetically distinct mouse strains that exhibit susceptibility (C57BL/6J) or resistance (PWK/PhJ) to cognitive decline during aging. Across both strains, synapse density on CA1-to-PFC projection neurons appeared completely intact with age. In contrast, we found synapse loss on PFC-to-nucleus reuniens (RE) projection neurons from aged C57BL/6J but not PWK/PhJ mice. Moreover, synapses from aged PWK/PhJ mice but not from C57BL/6J exhibited altered morphologies that suggest increased efficiency to drive depolarization in the parent dendrite. Our findings suggest resistance to age-related cognitive decline results in part by age-related synaptic adaptations, and identification of these mechanisms in PWK/PhJ mice could uncover new therapeutic targets for promoting successful cognitive aging and extending human health span.
Comments
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.