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

Neurobiology of Disease

卷:158

D.C. Consoli¹  S. Dixit²  W.P. Nobis²  R.A. Buchanan²  F.E. Harrison³  J.M. May⁴  J.M. Wilcox⁴  A.A. Tienda⁴ 

[1] Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States of America;

[2] Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, United States of America;

[3] Program in Neuroscience, Vanderbilt University, Nashville, TN, United States of America;

关键词: Alzheimer's disease;    Glutamate;    Memory;    Behavior;    Mouse;    EEG;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown