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Altered synaptic glutamate homeostasis contributes to cognitive decline in young APP/PSEN1 mice

Authors
  • Wilcox, J.M.1, 2
  • Consoli, D.C.1
  • Tienda, A.A.2
  • Dixit, S.2
  • Buchanan, R.A.1
  • May, J.M.2
  • Nobis, W. P.3
  • Harrison, F.E.2
  • 1 Program in Neuroscience, Vanderbilt University, Nashville, TN, United States of America
  • 2 Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States of America
  • 3 Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, United States of America
Type
Published Article
Journal
Neurobiology of Disease
Publisher
Elsevier
Publication Date
Aug 24, 2021
Volume
158
Pages
105486–105486
Identifiers
DOI: 10.1016/j.nbd.2021.105486
PMID: 34450329
PMCID: PMC8457528
Source
PubMed Central
Keywords
Disciplines
  • Article
License
Unknown

Abstract

Non-convulsive epileptiform activity is a common and under-studied comorbidity of Alzheimer’s disease that may significantly contribute to onset of clinical symptoms independently of other neuropathological features such as β-amyloid deposition. We used repeated treatment with low dose kainic acid (KA) to trigger subthreshold epileptiform activity in young (less than 6 months) wild-type (WT) and APP/PSEN1 mice to test the role of disruption to the glutamatergic system in epileptiform activity changes and the development of memory deficits. Short-term repeated low-dose KA (five daily treatments with 5 mg/kg, IP) impaired long-term potentiation in hippocampus of APP/PSEN1 but not WT mice. Long-term repeated low-dose KA (fourteen weeks of bi-weekly treatment with 7.5–10 mg/kg) led to high mortality in APP/PSEN1 mice. KA treatment also impaired memory retention in the APP/PSEN1 mice in a Morris water maze task under cognitively challenging reversal learning conditions where the platform was moved to a new location. Four weeks of bi-weekly treatment with 5 mg/kg KA also increased abnormal spike activity in APP/PSEN1 and not WT mice but did not impact sleep/wake behavioral states. These findings suggest that hyperexcitability in Alzheimer’s disease may indeed be an early contributor to cognitive decline that is independent of heavy β-amyloid-plaque load, which is absent in APP/PSEN1 mice under 6 months of age.

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