Entering a new era of quantifying glutamate clearance in health and disease

Brymer, Kyle J.; Barnes, Jocelyn R.; Parsons, Matthew

doi:10.1002/jnr.24810

Cited by 14 publications

(13 citation statements)

References 172 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While the present review focused on wtHTT’s role at the pre- and postsynapse, it is well-established that many synapses exist in a tripartite configuration with astrocytes playing an essential role in synaptic function. For example, perisynaptic astrocytic processes dictate the spatial spread and temporal profile of extracellular glutamate transients following synaptic release (for a recent review, see Brymer et al, 2021 ). Astrocyte dysfunction has been well-documented in HD ( Khakh et al, 2017 ), and expressing mHTT specifically in astrocytes can impair astrocytic BDNF release ( Hong et al, 2016 ) and recapitulate many key features of the HD-like phenotype in mice ( Bradford et al, 2009 ).…”

Section: Huntingtin Loss In Adulthood: Is It Safe?mentioning

confidence: 99%

Huntingtin and the Synapse

Barron

Hurley

Parsons

2021

Front. Cell. Neurosci.

Self Cite

View full text Add to dashboard Cite

Huntington disease (HD) is a monogenic disease that results in a combination of motor, psychiatric and cognitive symptoms. HD is caused by a CAG trinucleotide repeat expansion in the huntingtin (HTT) gene, which results in the production of a pathogenic mutant HTT protein (mHTT). Although there is no cure at present for HD, a number of RNA-targeting therapies have recently entered clinical trials which aim to lower mHTT production through the use of antisense oligonucleotides (ASOs) and RNAi. However, many of these treatment strategies are non-selective in that they cannot differentiate between non-pathogenic wild type HTT (wtHTT) and the mHTT variant. As HD patients are already born with decreased levels of wtHTT, these genetic therapies may result in critically low levels of wtHTT. The consequence of wtHTT reduction in the adult brain is currently under debate, and here we argue that wtHTT loss is not well-tolerated at the synaptic level. Synaptic dysfunction is an extremely sensitive measure of subsequent cell death, and is known to precede neurodegeneration in numerous brain diseases including HD. The present review focuses on the prominent role of wtHTT at the synapse and considers the consequences of wtHTT loss on both pre- and postsynaptic function. We discuss how wtHTT is implicated in virtually all major facets of synaptic neurotransmission including anterograde and retrograde transport of proteins to/from terminal buttons and dendrites, neurotransmitter release, endocytic vesicle recycling, and postsynaptic receptor localization and recycling. We conclude that wtHTT presence is essential for proper synaptic function.

show abstract

Section: Huntingtin Loss In Adulthood: Is It Safe?mentioning

confidence: 99%

Huntingtin and the Synapse

Barron

Hurley

Parsons

2021

Front. Cell. Neurosci.

Self Cite

View full text Add to dashboard Cite

show abstract

“…1E) were evoked by 5 pulses of electrical stimulation (100 Hz; 75 µA) applied to the Schaffer collaterals, and we monitored the glutamate response in baseline conditions and then to increasing sub-saturating concentrations of DHK. The decay tau of evoked iGluSnFR transients were used to quantify relative changes in the rate of glutamate clearance as described previously (Armbruster et al, 2016; Brymer et al, 2021; Pinky et al, 2018). iGluSnFR decay was more sensitive to partial GLT-1 inhibition when iGluSnFR was expressed presynaptically compared to postsynaptically (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In the 3xTg mouse model of AD, GLT-1 dysfunction slowed glutamate clearance at presynaptic but not postsynaptic microenvironments, resulting in presynaptic mGluR overactivation that opposed short-term plasticity. As GLT-1 dysfunction is implicated in numerous brain diseases in addition to AD (Brymer et al, 2021;Takahashi et al, 2015), our experiments may also have broader implications for presynaptic vulnerability in a range of disease states.…”

Section: Introductionmentioning

confidence: 93%

“…Our low concentration DHK experiments above suggest partial GLT-1 inhibition slows glutamate clearance to a greater extent at presynaptic compared to postsynaptic microenvironments. GLT-1 function and/or expression is partially decreased in a variety of neurodegenerative diseases, including AD (Brymer et al, 2021). Therefore, we hypothesized that a similar presynaptic vulnerability to glutamate uptake deficits may be apparent in 3xTg mice, a commonly-used mouse model of AD that presents with age-dependent amyloid and tau pathology (Oddo et al, 2003).…”

Section: Impaired Glutamate Clearance At Presynaptic Microenvironment...mentioning

confidence: 99%

See 1 more Smart Citation

Asymmetric dysregulation of glutamate dynamics across the synaptic cleft in a mouse model of Alzheimer disease

Brymer

Hurley

Barron

et al. 2022

Preprint

View full text Add to dashboard Cite

SummaryMost research on glutamate spillover focuses on the deleterious consequences of postsynaptic glutamate receptor overactivation. However, two decades ago, it was noted that the glial coverage of hippocampal synapses is asymmetric: astrocytic coverage of postsynaptic sites exceeds coverage of presynaptic sites by a factor of four. The fundamental relevance of this glial asymmetry remains poorly understood. Here, we used the glutamate biosensor iGluSnFR, and restricted its expression to either CA3 or CA1 neurons to visualize glutamate dynamics at pre- and postsynaptic microenvironments, respectively. We demonstrate that inhibition of the primarily astrocytic glutamate transporter-1 (GLT-1) slows glutamate clearance to a greater extent at presynaptic compared to postsynaptic membranes. GLT-1 expression was reduced early in a mouse model of AD, resulting in slower glutamate clearance rates at presynaptic but not postsynaptic membranes that opposed presynaptic short-term plasticity. Overall, our data demonstrate that the presynapse is particularly vulnerable to GLT-1 dysfunction and may have implications for presynaptic impairments in a variety of brain diseases.

show abstract

“…Failure in clear-ance of the residuals leads to accumulation of the neurotransmitters and ions. Excessive buildup of excitatory neurotransmitter such as glutamate is toxic to neurons and eventually causes neurodegenerative diseases [57]. High concentration of extracellular potassium ion depolarizes the membrane potential and contributes to the hyperexcitability of local neurons [58].…”

Section: Alteration Of Astrocyte Functionmentioning

confidence: 99%

Non-Cell Autonomous and Epigenetic Mechanisms of Huntington’s Disease

Kim

Yousefian-Jazi

Choi

et al. 2021

IJMS

View full text Add to dashboard Cite

Huntington’s disease (HD) is a rare neurodegenerative disorder caused by an expansion of CAG trinucleotide repeat located in the exon 1 of Huntingtin (HTT) gene in human chromosome 4. The HTT protein is ubiquitously expressed in the brain. Specifically, mutant HTT (mHTT) protein-mediated toxicity leads to a dramatic degeneration of the striatum among many regions of the brain. HD symptoms exhibit a major involuntary movement followed by cognitive and psychiatric dysfunctions. In this review, we address the conventional role of wild type HTT (wtHTT) and how mHTT protein disrupts the function of medium spiny neurons (MSNs). We also discuss how mHTT modulates epigenetic modifications and transcriptional pathways in MSNs. In addition, we define how non-cell autonomous pathways lead to damage and death of MSNs under HD pathological conditions. Lastly, we overview therapeutic approaches for HD. Together, understanding of precise neuropathological mechanisms of HD may improve therapeutic approaches to treat the onset and progression of HD.

show abstract

Entering a new era of quantifying glutamate clearance in health and disease

Cited by 14 publications

References 172 publications

Huntingtin and the Synapse

Huntingtin and the Synapse

Asymmetric dysregulation of glutamate dynamics across the synaptic cleft in a mouse model of Alzheimer disease

Non-Cell Autonomous and Epigenetic Mechanisms of Huntington’s Disease

Contact Info

Product

Resources

About