Mapping synaptic glutamate transporter dysfunction in vivo to regions surrounding Aβ plaques by iGluSnFR two-photon imaging

Hefendehl, Jasmin K.; LeDue, Jeffrey; Ko, Rebecca W.Y.; Mahler, Jasmin; Murphy, Timothy H.; MacVicar, Brian A.

doi:10.1038/ncomms13441

Cited by 125 publications

(113 citation statements)

References 50 publications

(79 reference statements)

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“…We expressed GluSnFR in either astrocytes or neurons using injections of cell type-specific viruses (AAV1-GFA(ABC(1)D)-iGluSnFR and AAV1-hsyn-iGluSnFR, respectively) and carried out 2P imaging of spontaneous activity in acute cortical slices. Distinct morphological differences between astrocytic and neuronal expression of GluSnFR were evident, as has been observed previously 8,24,25 (Fig. 5a).…”

Section: Astrocytic and Neuronal Expression Of Glusnfr Reveals Differsupporting

confidence: 85%

An event-based paradigm for analyzing fluorescent astrocyte activity uncovers novel single-cell and population-level physiology

Wang

DelRosso²,

Vaidyanathan³

et al. 2018

Preprint

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Recent work examining astrocytic physiology centers on fluorescence imaging approaches, due to development of sensitive fluorescent indicators and observation of spatiotemporally complex calcium and glutamate activity. However, the field remains hindered in fully characterizing these dynamics, both within single cells and at the population-level, because of the insufficiency of current region-of-interestbased approaches to describe activity that is often spatially unfixed, size-varying, and propagative. Here, we present a paradigm-shifting analytical framework that releases astrocyte biologists from ROI-based tools. Astrocyte Quantitative Analysis (AQuA) software enables users to take an event-based approach to accurately capture and quantify the irregular activity observed in astrocyte imaging datasets. We apply AQuA to a range of ex vivo and in vivo imaging data, and uncover previously undescribed physiological phenomena in each. Since AQuA is data-driven and based on machine learning principles, it can be applied across model organisms, fluorescent indicators, experimental modes, and imaging resolutions and speeds, enabling researchers to elucidate fundamental astrocyte physiology.

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Section: Astrocytic and Neuronal Expression Of Glusnfr Reveals Differsupporting

confidence: 85%

An event-based paradigm for analyzing fluorescent astrocyte activity uncovers novel single-cell and population-level physiology

Wang

DelRosso²,

Vaidyanathan³

et al. 2018

Preprint

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“…Hence the neurotoxic microenvironment encompassing Aβ aggregates were substantially improved in CEF received group of mice. Hefendehl et al, 2016 Amyotrophic lateral sclerosis (ALS). A multi-phase randomized trial of human-subjects diagnosed with ALS.…”

Section: Ace2mentioning

confidence: 99%

Repurposing of the β-Lactam Antibiotic, Ceftriaxone for Neurological Disorders: A Review

2019

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To date, there is no cure or disease-modifying agents available for most well-known neurological disorders. Current therapy is typically focused on relieving symptoms and supportive care in improving the quality of life of affected patients. Furthermore, the traditional de novo drug discovery technique is more challenging, particularly for neurological disorders. Therefore, the repurposing of existing drugs for these conditions is believed to be an efficient and dynamic approach that can substantially reduce the investments spent on drug development. Currently, there is emerging evidence that suggests the potential effect of a beta-lactam antibiotic, ceftriaxone (CEF), to alleviate the symptoms of different experimentally-induced neurological disorders: Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, epileptic-seizure, brain ischemia, traumatic brain injuries, and neuropathic pain. CEF also affects the markers of oxidative status and neuroinflammation, glutamatergic systems as well as various aggregated toxic proteins involved in the pathogenesis of different neurological disorders. Moreover, it was found that CEF administration to drug dependent animal models improved the withdrawal symptoms upon drug discontinuation. Thus, this review aimed to describe the effects of CEF against multiple models of neurological illnesses, drug dependency, and withdrawal. It also emphasizes the possible mechanisms of neuroprotective actions of CEF with respective neurological maladies.

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“…Moreover, A causes synaptic instability, a 'shrinkage of spines' and synaptic loss, which are accompanied by a reduction of LTP and increased LTD both in vitro and in vivo [10][11][12] . Counterintuitively, A can trigger an 'aberrant' increase in neuronal activity both acutely as well as under chronic conditions, such as in transgenic mouse models, which has been suggested to result from the activation of NMDA and AMPA receptors 1,[13][14][15][16] through increased glutamate release probability 17 or blockage of glutamate uptake [18][19][20] . If direct stimulation of glutamate receptors was the main driver of aberrantly increased neuronal activity, one would expect at least initially a subsequent desensitization and/or downregulation of these receptors and consequently a normalization of the altered neuronal activity as a homeostatic response 21 .…”

Section: Introductionmentioning

confidence: 99%

Long-term dynamics of aberrant neuronal activity in Alzheimer’s disease

Korzhova

Marinković

Goltstein

et al. 2019

Preprint

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Alzheimer's disease (AD) is associated with aberrant neuronal activity levels. How those activity alterations emerge and how stable they are over time in vivo, however, remains elusive to date. To address these questions we chronically recorded the activity from identified neurons in cortex of awake APPPS1 transgenic mice and their non-transgenic littermates over the course of 4 weeks by means of calcium imaging. Surprisingly, aberrant neuronal activity was very stable over time. Moreover, we identified a slow progressive gain of activity of former intermediately active neurons as the main source of new highly active neurons. Interestingly, fluctuations in neuronal activity were independent from amyloid plaque proximity, but aberrant activity levels were more likely to persist close to plaques. These results support the notion that neuronal network pathology observed in AD patients is the consequence of stable single cell aberrant neuronal activity, a finding of potential therapeutic relevance.

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Mapping synaptic glutamate transporter dysfunction in vivo to regions surrounding Aβ plaques by iGluSnFR two-photon imaging

Cited by 125 publications

References 50 publications

An event-based paradigm for analyzing fluorescent astrocyte activity uncovers novel single-cell and population-level physiology

An event-based paradigm for analyzing fluorescent astrocyte activity uncovers novel single-cell and population-level physiology

Repurposing of the β-Lactam Antibiotic, Ceftriaxone for Neurological Disorders: A Review

Long-term dynamics of aberrant neuronal activity in Alzheimer’s disease

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