Defective age-dependent metaplasticity in a mouse model of alzheimer’s disease

Andrea Megill, Trinh Tran, Kiara Eldred, Nathanael J. Lee, Philip C. Wong, Hyang Sook Hoe, Alfredo Kirkwood, Hey Kyoung Lee

Research output: Contribution to journalArticlepeer-review

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[1]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.

Original languageEnglish (US)
Pages (from-to)11346-11357
Number of pages12
JournalJournal of Neuroscience
Volume35
Issue number32
DOIs
StatePublished - Aug 12 2015

Keywords

  • AD
  • APPswe
  • LTD
  • LTP
  • PS1ΔE9
  • Pull–push metaplasticity
  • Sliding threshold

ASJC Scopus subject areas

  • Neuroscience(all)

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