Dynamic regulation of plasticity thresholds in a neuronal population is critical for the formation of long-term plasticity and memory and is achieved by mechanisms such as metaplasticity. Metaplasticity tunes the synapses to undergo changes that are necessary prerequisites for memory storage under physiological and pathological conditions. Here we discovered that, in amyloid precursor protein (APP)/presenilin-1 (PS1) mice (age 3-4 mo), a prominent mouse model of Alzheimer's disease (AD), late long-term potentiation (LTP; L-LTP) and its associative plasticity mechanisms such as synaptic tagging and capture (STC) were impaired already in presymptomatic mice. Interestingly, late long-term depression (LTD; L-LTD) was not compromised, but the positive associative interaction of LTP and LTD, cross-capture, was altered in these mice. Metaplastic activation of ryanodine receptors (RyRs) in these neurons reestablished L-LTP and STC. We propose that RyRmediated metaplastic mechanisms can be considered as a possible therapeutic target for counteracting synaptic impairments in the neuronal networks during the early progression of AD.A lzheimer's disease (AD), the most frequent form of dementia, is an age-related neurodegenerative disorder clinically characterized by early declarative memory deficits, followed by deterioration of other cognitive functions (1). The memory loss in AD is characterized by extracellular accumulation of amyloid β protein (Aβ) in the hippocampus and cerebral cortex preceding neurodegeneration (2, 3). Increasing evidence suggests that soluble forms of Aβ interfere with hippocampal synaptic plasticity mechanisms known to mediate learning and memory processes, including long-term potentiation (LTP) and long-term depression (LTD) of excitatory synaptic transmission (4-8). In particular, the protein synthesis-dependent late phase of LTP (L-LTP) is impaired in the hippocampus of various AD transgenic mouse models and in Aβ-treated hippocampal slices (4, 9), whereas LTD is facilitated (10) or not altered (10-12). It has been reported recently that Aβ-induced inhibition of LTP is mediated by extrasynaptic NMDA receptor activity, which prevents phosphorylation of the transcription factor cAMP response element-binding protein (13,14).Synaptic plasticity can be governed by a previous activity of the same postsynaptic neuron or neural network, a phenomenon referred to as metaplasticity (15). Metaplasticity orchestrates multiple aspects of functional plasticity and thus promotes long-term memory storage (16). For instance, inducing metaplasticity by activating ryanodine (RYA) receptors (RyRs) with its agonist RYA in hippocampal CA3-CA1 synapses lowers the threshold of LTP, resulting in enhanced LTP induction and persistence (17,18). In addition, metaplasticity can influence processes of associative memory storage as in the case for synaptic tagging and capture (STC) (17). STC is defined as the associative interactions between two independent sets of synapses within the same neuronal network, in which a synaptic...