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

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⌬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 Ca 2ϩ -permeable AMPA receptors. We propose that the main synaptic defect in AD mouse models is due to their inability to undergo developmental metaplasticity.

Metaplasticity mechanisms restore plasticity and associativity in an animal model of Alzheimer’s disease

“…Our study provides compelling evidence that, even in AD, the activated neural network is capable of incorporating metaplastic states, thereby compensating dysregulated synaptic plasticity in the hippocampal memory circuitry. Our findings are in agreement with recent observation by Megill et al in which the authors proposed that the synaptic defect occurring in AD mouse models may result from the inability of the synaptic populations to undergo metaplasticity, especially during developmental stages (35). We propose that enabling a synaptic population for metaplasticity can reestablish plasticity and associative plasticity in AD mouse models.…”

“…for inducing plasticity (35). RyR priming rescues it by increasing calcium level, thereby lowering the threshold for inducing plasticity and bringing L-LTP back to the positive part of the BCM curve.…”

NMDA Receptor-Dependent LTD Requires Transient Synaptic Incorporation of Ca 2+ -Permeable AMPARs Mediated by AKAP150-Anchored PKA and Calcineurin

“…Meta-plastic changes conferred by CP-AMPARs include enhanced LTP at hippocampal synapses (Megill et al, 2015; Sanderson et al, 2012) and the ability to express a unique mGluR1-mediated mechanism that removes CP-AMPARs from synapses in the amygdala, nucleus accumbens, ventral tegmentum, and cerebellum (Bellone et al, 2011; Clem and Huganir, 2013; Kelly et al, 2009; Loweth et al, 2013). Here we show that CP-AMPAR recruitment to synapses can also positively regulate NMDAR-dependent LTD, but only if CP-AMPARs remain in the synapse transiently, such that the change in meta-plasticity is brief.…”

Amyloid-β effects on synapses and memory require AMPA receptor subunit GluA3

“…In such a scenario, neurons that are deprived of synaptic input increase their synaptic GluA2/3 levels, and, conversely, neurons that are hyperactive counteract by lowering the number of GluA2/3s at synapses. It has recently been suggested that ADrelated synaptic and memory deficits may arise from defects in homeostatic plasticity (39,40). Possibly Aβ oligomers mediate a persistent synaptic downscaling by reducing the levels of GluA2/3s at synapses irrespective of the history of neuronal activity.…”