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

Autor: Wilcox JM; Program in Neuroscience, Vanderbilt University, Nashville, TN, United States of America; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States of America., Consoli DC; Program in Neuroscience, Vanderbilt University, Nashville, TN, United States of America., Tienda AA; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States of America., Dixit S; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States of America., Buchanan RA; Program in Neuroscience, Vanderbilt University, Nashville, TN, United States of America., May JM; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States of America., Nobis WP; Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, United States of America., Harrison FE; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States of America. Electronic address: fiona.harrison@vumc.org.
Jazyk: angličtina
Zdroj: Neurobiology of disease [Neurobiol Dis] 2021 Oct; Vol. 158, pp. 105486. Date of Electronic Publication: 2021 Aug 24.
DOI: 10.1016/j.nbd.2021.105486
Abstrakt: 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 sub-threshold 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.
(Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: