Reduced presynaptic vesicle stores mediate cellular and network plasticity defects in an early-stage mouse model of Alzheimer’s disease

Autor: Daniel A. Peterson, Barbara M. Vertel, Corinne Schneider, William N. Frost, Daniel T. Christian, Nicolas Kapecki, Grace E. Stutzmann, Rosalind Helfrich, Shannon Riley, Anthony R. West, Sarah Mustaly-Kalimi, Figen A. Seiler, Evan S. Hill, Shreaya Chakroborty
Rok vydání: 2019
Předmět:
Male
0301 basic medicine
Hippocampus
lcsh:Geriatrics
Biology
Hippocampal formation
Network imaging
Spines
Synaptic Transmission
Synaptic vesicle
lcsh:RC346-429
Mouse model
Synapse
Mice
03 medical and health sciences
Cellular and Molecular Neuroscience
2-photon imaging
0302 clinical medicine
Alzheimer Disease
Postsynaptic potential
Electron microscopy
medicine
Animals
Calcium Signaling
Cognitive decline
Molecular Biology
lcsh:Neurology. Diseases of the nervous system
Neuronal Plasticity
Synaptic
Synaptic vesicles
lcsh:RC952-954.6
Disease Models
Animal
030104 developmental biology
medicine.anatomical_structure
Ryanodine receptor
Schaffer collateral
Synaptic plasticity
Calcium
Female
Neurology (clinical)
Patch clamp
Alzheimer’s disease
Neuroscience
Short-term plasticity
030217 neurology & neurosurgery
Research Article
Zdroj: Molecular Neurodegeneration
Molecular Neurodegeneration, Vol 14, Iss 1, Pp 1-21 (2019)
ISSN: 1750-1326
DOI: 10.1186/s13024-019-0307-7
Popis: Background Identifying effective strategies to prevent memory loss in AD has eluded researchers to date, and likely reflects insufficient understanding of early pathogenic mechanisms directly affecting memory encoding. As synaptic loss best correlates with memory loss in AD, refocusing efforts to identify factors driving synaptic impairments may provide the critical insight needed to advance the field. In this study, we reveal a previously undescribed cascade of events underlying pre and postsynaptic hippocampal signaling deficits linked to cognitive decline in AD. These profound alterations in synaptic plasticity, intracellular Ca2+ signaling, and network propagation are observed in 3–4 month old 3xTg-AD mice, an age which does not yet show overt histopathology or major behavioral deficits. Methods In this study, we examined hippocampal synaptic structure and function from the ultrastructural level to the network level using a range of techniques including electron microscopy (EM), patch clamp and field potential electrophysiology, synaptic immunolabeling, spine morphology analyses, 2-photon Ca2+ imaging, and voltage-sensitive dye-based imaging of hippocampal network function in 3–4 month old 3xTg-AD and age/background strain control mice. Results In 3xTg-AD mice, short-term plasticity at the CA1-CA3 Schaffer collateral synapse is profoundly impaired; this has broader implications for setting long-term plasticity thresholds. Alterations in spontaneous vesicle release and paired-pulse facilitation implicated presynaptic signaling abnormalities, and EM analysis revealed a reduction in the ready-releasable and reserve pools of presynaptic vesicles in CA3 terminals; this is an entirely new finding in the field. Concurrently, increased synaptically-evoked Ca2+ in CA1 spines triggered by LTP-inducing tetani is further enhanced during PTP and E-LTP epochs, and is accompanied by impaired synaptic structure and spine morphology. Notably, vesicle stores, synaptic structure and short-term plasticity are restored by normalizing intracellular Ca2+ signaling in the AD mice. Conclusions These findings suggest the Ca2+ dyshomeostasis within synaptic compartments has an early and fundamental role in driving synaptic pathophysiology in early stages of AD, and may thus reflect a foundational disease feature driving later cognitive impairment. The overall significance is the identification of previously unidentified defects in pre and postsynaptic compartments affecting synaptic vesicle stores, synaptic plasticity, and network propagation, which directly impact memory encoding. Electronic supplementary material The online version of this article (10.1186/s13024-019-0307-7) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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