AMPA receptor downscaling at the onset of Alzheimer’s disease pathology in double knockin mice

Abstract

It is widely thought that Alzheimer's disease (AD) begins as a malfunction of synapses, eventually leading to cognitive impairment and dementia. Homeostatic synaptic scaling is a mechanism that could be crucial at the onset of AD but has not been examined experimentally. In this process, the synaptic strength of a neuron is modified so that the overall excitability of the cell is maintained. Here, we investigate whether synaptic scaling mediated by L-␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) contributes to pathology in double knockin (2؋KI) mice carrying human mutations in the genes for amyloid precursor protein and presenilin-1. By using whole-cell recordings, we show that 2؋KI mice exhibit age-related downscaling of AMPARmediated evoked currents and spontaneous, miniature currents. Electron microscopic analysis further corroborates the synaptic AMPAR decrease. Additionally, 2؋KI mice show age-related deficits in bidirectional plasticity (long-term potentiation and longterm depression) and memory flexibility. These results suggest that AMPARs are important synaptic targets for AD and provide evidence that cognitive impairment may involve downscaling of postsynaptic AMPAR function.amyloid precursor protein ͉ glutamate ͉ presenilin E xtensive work on Alzheimer's disease (AD) has led to the hypothesis that the memory failure exhibited by patients in the early stages of AD results from synaptic disruption (1-3), without frank neuronal loss, which is caused by toxicity of the 42-aa variant of the amyloid ␤ protein (A␤ 42 ). Work in AD models (4) shows that A␤ 42 impairs synaptic plasticity in brain regions, such as the hippocampus, that are recognized early targets for AD. Transgenic (Tg) mice with familial AD mutations display disruptions of long-term potentiation (LTP), an electrophysiological correlate of memory encoding (5). The LTP impairment occurs before deposition of A␤ plaques (4, 6), making it a sensitive marker for early AD dysfunction. Notably, the late phase of LTP (called expression) is highly susceptible to disruption (6-9). LTP expression relies on alterations of L-␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptors (AMPARs), including phosphorylation by kinases and recruitment of AMPARs to the synaptic membrane (10). Conversely, AMPAR removal is thought to mediate the activitydependent decrease of excitatory transmission (11), which is elicited by the paradigm of long-term depression (LTD) (12). Importantly, LTD has been scarcely studied in AD models (4, 13), particularly Tg-AD mice.Recently, AMPARs have been implicated in a slower form of synaptic plasticity, termed homeostatic synaptic scaling, in which the total synaptic strength of a neuron is modified to regulate its excitability (14). Synaptic scaling involves, among other factors, the postsynaptic insertion and removal of AMPARs and changes in the turnover rate of functional receptors (14-16). Adjustments by synaptic scaling operate in vivo (17) and seem critical for regulating synaptic strength during lear...

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