Defective Age-Dependent Metaplasticity in a Mouse Model of Alzheimer's Disease.
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;PS1ΔE9 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 Ca(2+)-permeable AMPA receptors. We propose that the main synaptic defect in AD mouse models is due to their inability to undergo developmental metaplasticity.


CONCLUSIONS
This work offers a new insight that metaplasticity defects are central to synaptic dysfunctions seen in AD mouse models. In particular, we demonstrate that the apparent differences in LTP/LTD magnitude seen across ages in AD transgenic mouse models reflect the inability to undergo a normal developmental shift in metaplasticity.
Solomon H. Snyder Department of Neuroscience, Zanvyl-Krieger Mind/Brain Institute, and.
Andrea
A
Megill
Solomon H. Snyder Department of Neuroscience, Zanvyl-Krieger Mind/Brain Institute, and.
Trinh
T
Tran
Department of Biology, Johns Hopkins University, Baltimore, Maryland 21218.
Kiara
http://orcid.org/0000-0002-4067-8639
K
Eldred
Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20057, and.
Nathanael J
http://orcid.org/0000-0002-1772-1723
NJ
Lee
Solomon H. Snyder Department of Neuroscience, Zanvyl-Krieger Mind/Brain Institute, and Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21205.
Philip C
PC
Wong
Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20057, and.
Hyang-Sook
HS
Hoe
Solomon H. Snyder Department of Neuroscience, Zanvyl-Krieger Mind/Brain Institute, and.
Alfredo
A
Kirkwood
Solomon H. Snyder Department of Neuroscience, Zanvyl-Krieger Mind/Brain Institute, and Department of Biology, Johns Hopkins University, Baltimore, Maryland 21218, heykyounglee@jhu.edu.
Hey-Kyoung
http://orcid.org/0000-0002-5554-983X
HK
Lee
D000367:Age Factors; D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology*; D017774:Long-Term Potentiation / Q000502:physiology*; D036881:Long-Term Synaptic Depression / Q000502:physiology*; D008297:Male; D051379:Mice; D010766:Phosphorylation; D018091:Receptors, AMPA / Q000378:metabolism; D013569:Synapses / Q000502:physiology*
D018091:Receptors, AMPA; D002118:Calcium
AD; APPswe;PS1ΔE9; LTD; LTP; pull–push metaplasticity; sliding threshold