Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 21, Pages 5527-5532Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1613700114
Keywords
metaplasticity; hippocampus; synaptic tagging; APP/PS1 mice; L-LTP
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Funding
- Deutsche Forschungsgemeinschaft [SA 1853/1-1, KO 1674/10-2]
- National Medical Research Council (NMRC) Collaborative Research Grants [NMRC-CBRG-0041/2013, NMRC-CBRG-0099-2015]
- National University of Singapore, University Strategic Research [DPRT/944/09/14]
- National University of Singapore Yong Loo Lin School of Medicine Aspiration Fund [R-185-000-271-720]
- Deutscher Akademischer Austausch Dienst (DAAD) Fellowship [A/09/98265]
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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 RyR-mediated metaplastic mechanisms can be considered as a possible therapeutic target for counteracting synaptic impairments in the neuronal networks during the early progression of AD.
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