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  • Perspective
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Imbalance between firing homeostasis and synaptic plasticity drives early-phase Alzheimer’s disease

Abstract

During recent years, the preclinical stage of Alzheimer's disease (AD) has become a major focus of research. Continued failures in clinical trials and the realization that early intervention may offer better therapeutic outcome triggered a conceptual shift from late-stage AD pathology to early-stage pathophysiology. While much effort has been directed at understanding the factors initiating AD, little is known about the principle basis underlying the disease progression at its early stages. In this Perspective, we suggest a hypothesis to explain the transition from ‘silent’ signatures of aberrant neural circuit activity to clinically evident memory impairments. Namely, we propose that failures in firing homeostasis and imbalance between firing stability and synaptic plasticity in cortico-hippocampal circuits represent the driving force of early disease progression. We analyze the main types of possible homeostatic failures and provide the essential conceptual framework for examining the causal link between dysregulation of firing homeostasis, aberrant neural circuit activity and memory-related plasticity impairments associated with early AD.

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Fig. 1: Firing homeostasis and its failure.
Fig. 2: Experimental framework for investigating firing homeostasis failures.
Fig. 3: Decoupling of Ca2+ sensors from spiking activity and stability.
Fig. 4: FHP hypothesis: possible transitions from normal to early AD states.
Fig. 5: Balance of firing stability–synaptic plasticity and its disruption in early AD stages.

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Acknowledgements

We thank Y. Nir and the I.S. lab members for comments on the manuscript. This work was supported by research grants to I.S from the European Research Council starting (281403) and consolidator (724866) grants, the Legacy Heritage Biomedical Program of the Israel Science Foundation (1849/17), the Israel Science Foundation (398/13) and the Binational Science Foundation (2013244). I.S. is grateful to Sheila and Denis Cohen Charitable Trust and Rosetrees Trust of the UK for their support.

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Styr, B., Slutsky, I. Imbalance between firing homeostasis and synaptic plasticity drives early-phase Alzheimer’s disease. Nat Neurosci 21, 463–473 (2018). https://doi.org/10.1038/s41593-018-0080-x

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