Local Efficacy of Glutamate Uptake Decreases with Synapse Size

Herde, Michel K.; Bohmbach, Kirsten; Domingos, Cátia; Vana, Natascha; Komorowska-Müller, Joanna Agnieszka; Passlick, Stefan; Schwarz, Inna; Jackson, Colin J.; Dietrich, Dirk; Schwarz, Martin K.; Henneberger, Christian

doi:10.1016/j.celrep.2020.108182

Cited by 54 publications

(83 citation statements)

References 64 publications

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“…Thus, in situ glutamate dynamics are extremely complex and depend on many factors in addition to overall transporter expression levels. For example, glutamate clearance rates depend on the proximity of perisynaptic astrocytic processes to the synapse (Henneberger et al, 2020), synapse size (Herde et al, 2020), astrocyte resting membrane potential (Djukic et al, 2007), transporter surface mobility (Murphy-Royal et al, 2015) as well as the architecture and tortuosity of the extracellular space (Hrabětová, 2005). Posttranslational modifications of glutamate transporters, including phosphorylation and palmitoylation, can also influence transporter-mediated uptake (Casado et al, 1993;Huang et al, 2010;Pita-Almenar et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

The Effect of GLT-1 Upregulation on Extracellular Glutamate Dynamics

Wilkie

Barron

Brymer

et al. 2021

Front. Cell. Neurosci.

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Pharmacological upregulation of glutamate transporter-1 (GLT-1), commonly achieved using the beta-lactam antibiotic ceftriaxone, represents a promising therapeutic strategy to accelerate glutamate uptake and prevent excitotoxic damage in neurological conditions. While excitotoxicity is indeed implicated in numerous brain diseases, it is typically restricted to select vulnerable brain regions, particularly in early disease stages. In healthy brain tissue, the speed of glutamate uptake is not constant and rather varies in both an activity- and region-dependent manner. Despite the widespread use of ceftriaxone in disease models, very little is known about how such treatments impact functional measures of glutamate uptake in healthy tissue, and whether GLT-1 upregulation can mask the naturally occurring activity-dependent and regional heterogeneities in uptake. Here, we used two different compounds, ceftriaxone and LDN/OSU-0212320 (LDN), to upregulate GLT-1 in healthy wild-type mice. We then used real-time imaging of the glutamate biosensor iGluSnFR to investigate functional consequences of GLT-1 upregulation on activity- and regional-dependent variations in glutamate uptake capacity. We found that while both ceftriaxone and LDN increased GLT-1 expression in multiple brain regions, they did not prevent activity-dependent slowing of glutamate clearance nor did they speed basal clearance rates, even in areas characterized by slow uptake (e.g., striatum). Unexpectedly, ceftriaxone but not LDN decreased glutamate release in the cortex, suggesting that ceftriaxone may alter release properties independent of its effects on GLT-1 expression. In sum, our data demonstrate the complexities of glutamate uptake by showing that GLT-1 expression does not necessarily translate to accelerated uptake. Furthermore, these data suggest that the mechanisms underlying activity- and regional-dependent differences in glutamate dynamics are independent of GLT-1 expression levels.

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Section: Introductionmentioning

confidence: 99%

The Effect of GLT-1 Upregulation on Extracellular Glutamate Dynamics

Wilkie

Barron

Brymer

et al. 2021

Front. Cell. Neurosci.

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“…Conversely, it can be concluded that if the local transporter density is slightly up- or down-regulated, this will result in a shorter or larger SARGe. This connection puts astrocytes in an ideal position to tune synaptic cross-talk by strategic positioning of glutamate transporter molecules or their membranes, eg ( 67, 68 ).…”

Section: Discussionmentioning

confidence: 99%

Optical analysis of the action range of glutamate in the neuropil

Matthews

Sun

McMahon

et al. 2021

Preprint

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The wiring scheme is key to the function of the brain. Neurons are structurally wired by synapses and most synapses in the CNS are considered sufficiently isolated to avoid cross-talk to AMPA receptors of neighboring synapses. On the contrary, we show here with optical reporter proteins that the neurotransmitter glutamate regularly spreads far into the extracellular space (>1μm) after vesicular release. Together with 2P-glutamate uncaging our data suggest that multi-vesicular release rather regularly generates crosstalk responses at AMPA receptors of ~2-4 adjacent synapses (>70 synapses for NMDA receptors). Extracellular spread of glutamate is cooperative and coincident synaptic release events show enhanced spread and cause supra-additive activation of postsynapses. Thus, synaptic wiring of the brain seems to deviate more from point-to-point communication than previously reported and involves broadcasting information to very local neighborhoods which can stabilize learning performance and allow for integration of synaptic activity within the extracellular space.

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“…In contrast, invasion of the synaptic cleft by astrocytic processes in Connexin 30 knockout mice increased the control of synaptic transmission by glutamate uptake (Pannasch et al, 2014). Along these lines, we recently demonstrated that spine size negatively correlates with the local efficacy of glutamate uptake in the hippocampus (Herde et al, 2020). Another study suggested that rearrangements of the astrocytic cytoskeleton induced changes in glutamate uptake which were linked to altered activity of the Na + /K + -ATPase (Sheean et al, 2013).…”

Section: Localization Of Glutamate Transportersmentioning

confidence: 91%

“…However, after escaping the synaptic cleft, the radius of action of glutamate is determined by diffusion and the hindrance thereof either by physical barriers or by binding and uptake by transporters (Zheng et al, 2008;Scimemi and Beato, 2009). Hence, glutamate transporters located close to the synaptic cleft limit the diffusion of glutamate to extrasynaptic sites, where high-affinity N-methyl-D-aspartate receptors (NMDARs) and metabotropic glutamate receptors (mGluRs) are localized, and prevent the spillover to neighboring neurons (Scimemi et al, 2004;Zheng et al, 2008;Henneberger et al, 2020;Herde et al, 2020).…”

Section: Localization Of Glutamate Transportersmentioning

confidence: 99%

“…Thus, acute and/or transient metabolic stress can impair glutamate uptake substantially. This will promote local glutamate accumulation and glutamate spread into the tissue (Figure 1) because inhibition of glutamate uptake increases the lifetime of glutamate in the ECS and its spread (Henneberger et al, 2020;Herde et al, 2020). However, glutamate uptake is not the only mechanism that determines extracellular glutamate concentrations and their diffusion.…”

Section: Impairment Of Transporter Function Reduced Uptake and Reversal-ion Homeostasis And The Direction Of Glutamate Transportmentioning

confidence: 99%

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Disruption of Glutamate Transport and Homeostasis by Acute Metabolic Stress

Passlick

Rose

Petzold

et al. 2021

Front. Cell. Neurosci.

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High-affinity, Na+-dependent glutamate transporters are the primary means by which synaptically released glutamate is removed from the extracellular space. They restrict the spread of glutamate from the synaptic cleft into the perisynaptic space and reduce its spillover to neighboring synapses. Thereby, glutamate uptake increases the spatial precision of synaptic communication. Its dysfunction and the entailing rise of the extracellular glutamate concentration accompanied by an increased spread of glutamate result in a loss of precision and in enhanced excitation, which can eventually lead to neuronal death via excitotoxicity. Efficient glutamate uptake depends on a negative resting membrane potential as well as on the transmembrane gradients of the co-transported ions (Na+, K+, and H+) and thus on the proper functioning of the Na+/K+-ATPase. Consequently, numerous studies have documented the impact of an energy shortage, as occurring for instance during an ischemic stroke, on glutamate clearance and homeostasis. The observations range from rapid changes in the transport activity to altered expression of glutamate transporters. Notably, while astrocytes account for the majority of glutamate uptake under physiological conditions, they may also become a source of extracellular glutamate elevation during metabolic stress. However, the mechanisms of the latter phenomenon are still under debate. Here, we review the recent literature addressing changes of glutamate uptake and homeostasis triggered by acute metabolic stress, i.e., on a timescale of seconds to minutes.

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Local Efficacy of Glutamate Uptake Decreases with Synapse Size

Cited by 54 publications

References 64 publications

The Effect of GLT-1 Upregulation on Extracellular Glutamate Dynamics

The Effect of GLT-1 Upregulation on Extracellular Glutamate Dynamics

Optical analysis of the action range of glutamate in the neuropil

Disruption of Glutamate Transport and Homeostasis by Acute Metabolic Stress

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