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Defective Age-Dependent Metaplasticity in a Mouse Model of Alzheimer's Disease

Authors
Megill AndreaTran TrinhEldred KiaraLee Nathanael J.Wong Philip C.Hoe Hyang-SookKirkwood AlfredoLee Hey-Kyoung
Issue Date
Aug-2015
Publisher
SOC NEUROSCIENCE
Citation
JOURNAL OF NEUROSCIENCE, v.35, no.32, pp.11346 - 11357
Journal Title
JOURNAL OF NEUROSCIENCE
Volume
35
Number
32
Start Page
11346
End Page
11357
URI
http://scholarworks.bwise.kr/kbri/handle/2023.sw.kbri/874
ISSN
0270-6474
Abstract
Much of the molecular understanding of synaptic pathology in Alzheimer's disease (AD) comes from studies of various mouse models that express familial AD (FAD)-linked mutations, often in combinations. Most studies compare the absolute magnitudes of long-term potentiation (LTP) and long-term depression (LTD) to assess deficits in bidirectional synaptic plasticity accompanying FAD-linked mutations. However, LTP and LTD are not static, but their induction threshold is adjusted by overall neural activity via metaplasticity. Hence LTP/LTD changes in AD mouse models may reflect defects in metaplasticity processes. To determine this, we examined the LTP/LTD induction threshold in APPswe; PS1 Delta E9 transgenic (Tg) mice across two different ages. We found that in young Tg mice (1 month), LTP is enhanced at the expense of LTD, but in adults (6 months), the phenotype is reversed to promote LTD and reduce LTP, compared to age-matched wild-type (WT) littermates. The apparent opposite phenotype across age was due to an initial offset in the induction threshold to favor LTP and the inability to undergo developmental metaplasticity in Tg mice. In WTs, the synaptic modification threshold decreased over development to favor LTP and diminish LTD in adults. However, in Tg mice, the magnitudes of LTP and LTD stayed constant across development. The initial offset in LTP/LTD threshold in young Tg mice did not accompany changes in the LTP/LTD induction mechanisms, but altered AMPA receptor phosphorylation and appearance of Ca2+-permeable AMPA receptors. We propose that the main synaptic defect in AD mouse models is due to their inability to undergo developmental metaplasticity.
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연구본부 (퇴행성뇌질환 연구그룹)
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