Cognitive aging is associated with redistribution of synaptic weights in the hippocampus

Eric W. Buss, Nicola J. Corbett, Joshua G. Roberts, Natividad Ybarra, Timothy F. Musial, Dina Simkin, Elizabeth Molina-Campos, Kwang Jin Oh, Lauren L. Nielsen, Gelique D. Ayala, Sheila A. Mullen, Anise K. Farooqi, Gary X. D’Souza, Corinne L. Hill, Linda A. Bean, Annalise E. Rogalsky, Matthew L. Russo, Dani M. Curlik, Marci D. Antion, Craig WeissDane M. Chetkovich, M. Matthew Oh, John F. Disterhoft*, Daniel A. Nicholson

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


Behaviors that rely on the hippocampus are particularly susceptible to chronological aging, with many aged animals (including humans) maintaining cognition at a young adult-like level, but many others the same age showing marked impairments. It is unclear whether the ability to maintain cognition over time is attributable to brain maintenance, sufficient cognitive reserve, compensatory changes in network function, or some combination thereof. While network dysfunction within the hippocampal circuit of aged, learning-impaired animals is well-documented, its neurobiological substrates remain elusive. Here we show that the synaptic architecture of hippocampal regions CA1 and CA3 is maintained in a young adult-like state in aged rats that performed comparably to their young adult counterparts in both trace eyeblink conditioning and Morris water maze learning. In contrast, among learning-impaired, but equally aged rats, we found that a redistribution of synaptic weights amplifies the influence of autoassociational connections among CA3 pyramidal neurons, yet reduces the synaptic input onto these same neurons from the dentate gyrus. Notably, synapses within hippocampal region CA1 showed no group differences regardless of cognitive ability. Taking the data together, we find the imbalanced synaptic weights within hippocampal CA3 provide a substrate that can explain the abnormal firing characteristics of both CA3 and CA1 pyramidal neurons in aged, learning-impaired rats. Furthermore, our work provides some clarity with regard to how some animals cognitively age successfully, while others’ lifespans outlast their “mindspans.”

Original languageEnglish (US)
Article numbere1921481118
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number8
StatePublished - Feb 23 2021


  • Aging
  • Cognition
  • Hippocampus
  • Synapse

ASJC Scopus subject areas

  • General


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