Shaping of Signal Transmission at the Photoreceptor Synapse by EAAT2 Glutamate Transporters

Niklaus, Stephanie; Cadetti, Lucia; Berg, Colette vom; Lehnherr, André; Hotz, Adriana L.; Forster, Ian C.; Gesemann, Matthias

doi:10.1523/eneuro.0339-16.2017

Cited by 25 publications

(40 citation statements)

References 59 publications

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“…We used bacterial artificial chromosome (BAC)-recombineering to generate an slc1a2b fluorescent reporter line, TgBAC(slc1a2b:Citrine), expressing Citrine in the cytoplasm of RG ( Figure 1d and Figure S1) (Bussmann & Schulte-Merker, 2011). In slc1a2b:Citrine zebrafish, the fluorescent expression pattern appeared highly similar to that observed by slc1a2b mRNA in situ hybridization, showing cell bodies lining the ventricle and radial fibers extending throughout the brain (Figure 1d and Figure S1) (Franceschi et al, 2018;Gesemann, Lesslauer, Maurer, Schonthaler, & Neuhauss, 2010;McKeown et al, 2012;Niklaus et al, 2017;Rohrschneider, Elsen, & Prince, 2007). We next visualized lysosomes in RG of control and hexb crispants.…”

Section: Direct Mutagenesis Causes Hexb Enzyme Deficiency and Glialmentioning

confidence: 76%

Hexb enzyme deficiency leads to lysosomal abnormalities in radial glia and microglia in zebrafish brain development

Kuil

Martí

Mascaro

et al. 2019

Glia

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Sphingolipidoses are severe, mostly infantile lysosomal storage disorders (LSDs) caused by defective glycosphingolipid degradation. Two of these sphingolipidoses, Tay Sachs and Sandhoff diseases, are caused by β‐Hexosaminidase (HEXB) enzyme deficiency, resulting in ganglioside (GM2) accumulation and neuronal loss. The precise sequence of cellular events preceding, and leading to, neuropathology remains unclear, but likely involves inflammation and lysosomal accumulation of GM2 in multiple cell types. We aimed to determine the consequences of Hexb activity loss for different brain cell types using zebrafish. Hexb deficient zebrafish (hexb−/−) showed lysosomal abnormalities already early in development both in radial glia, which are the neuronal and glial progenitors, and in microglia. Additionally, at 5 days postfertilization, hexb−/− zebrafish showed reduced locomotor activity. Although specific oligosaccharides accumulate in the adult brain, hexb−/−) zebrafish are viable and apparently resistant to Hexb deficiency. In all, we identified cellular consequences of loss of Hexb enzyme activity during embryonic brain development, showing early effects on glia, which possibly underlie the behavioral aberrations. Hereby, we identified clues into the contribution of non‐neuronal lysosomal abnormalities in LSDs affecting the brain and provide a tool to further study what underlies the relative resistance to Hexb deficiency in vivo.

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Section: Direct Mutagenesis Causes Hexb Enzyme Deficiency and Glialmentioning

confidence: 76%

Hexb enzyme deficiency leads to lysosomal abnormalities in radial glia and microglia in zebrafish brain development

Kuil

Martí

Mascaro

et al. 2019

Glia

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“…This depolarization could be largely suppressed by 1 μM (2S, 3S)-3-[3-[4-(trifluoromethyl) benzoylamino]benzyloxy]aspartate (TFB-TBOA) (15.2% ± 3.1% of control, p < 0.01), a selective inhibitor of subtypes 1 and 2 of the excitatory amino acid transporters EAAT1 and EAAT2 (also called glutamate and aspartate transporter [GLAST] and glutamate transporter [GLT]-1, respectively) (Tsukada et al, 2005). Previous studies showed that in larval zebrafish, EAAT2 but not EAAT1 was consistently found to be expressed in the retina (Gesemann et al, 2010; Niklaus et al, 2017) and that both EAAT2a and 2b subtypes are expressed in MGCs but not in RGCs (Niklaus et al, 2017).…”

Section: Resultsmentioning

confidence: 99%

Müller Glial Cells Participate in Retinal Waves via Glutamate Transporters and AMPA Receptors

Zhang

Prober

et al. 2019

Cell Reports

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SUMMARY Retinal waves, the spontaneous patterned neural activities propagating among developing retinal ganglion cells (RGCs), instruct the activity-dependent refinement of visuotopic maps. Although it is known that the wave is initiated successively by amacrine cells and bipolar cells, the behavior and function of glia in retinal waves remain unclear. Using multiple in vivo methods in larval zebrafish, we found that Müller glial cells (MGCs) display wave-like spontaneous activities, which start at MGC processes within the inner plexiform layer, vertically spread to their somata and endfeet, and horizontally propagate into neighboring MGCs. MGC waves depend on glutamatergic signaling derived from bipolar cells. Moreover, MGCs express both glia-specific glutamate transporters and the AMPA subtype of glutamate receptors. The AMPA receptors mediate MGC calcium activities during retinal waves, whereas the glutamate transporters modulate the occurrence of retinal waves. Thus, MGCs can sense and regulate retinal waves via AMPA receptors and glutamate transporters, respectively.

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“…Under physiological conditions, glutamate is released in the synapses and subsequently taken up by excitatory amino acid transporters (EAATs) of mainly Müller glial cells but also other cell types, preventing excitotoxic concentrations. In the outer retina, extracellular glutamate is mainly transported into Müller cells through EAAT1/GLAST, but EAAT2/GLT-1 on glial and non-glial cells also contributes to glutamate recapture [32]. After the uptake of extracellular glutamate by Müller cells, intracellular glutamate can be released from glial cells by a cystine/glutamate antiporter, the x c − system, to import cystine to fuel glutathione synthesis necessary for anti-oxidant defense [33].…”

Section: Il-1β Disrupts Glutamate Homeostasis In Müller Glial Cellsmentioning

confidence: 99%

IL-1β induces rod degeneration through the disruption of retinal glutamate homeostasis

Charles-Messance

Blot

Couturier

et al. 2020

J Neuroinflammation

167

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Background: Age-related macular degeneration is characterized by the accumulation of subretinal macrophages and the degeneration of cones, but mainly of rods. We have previously shown that Mononuclear Phagocytesderived IL-1β induces rod photoreceptor cell death during experimental subretinal inflammation and in retinal explants exposed to IL-1β but the mechanism is unknown. Methods: Retinal explants were culture in the presence of human monocytes or IL-1β and photoreceptor cell survival was analyzed by TUNEL labeling. Glutamate concentration and transcription levels of gene involved in the homeostasis of glutamate were analyzed in cell fractions of explant cultured or not in the presence of IL-1β. Glutamate receptor antagonists were evaluated for their ability to reduce photoreceptor cell death in the presence of IL1-β or monocytes. Results: We here show that IL-1β does not induce death in isolated photoreceptors, suggesting an indirect effect. We demonstrate that IL-1β leads to glutamate-induced rod photoreceptor cell death as it increases the extracellular glutamate concentrations in the retina through the inhibition of its conversion to glutamine in Müller cells, increased release from Müller cells, and diminished reuptake. The inhibition of non-NMDA receptors completely and efficiently prevented rod apoptosis in retinal explants cultured in the presence of IL-1β or, more importantly, in vivo, in a model of subretinal inflammation. Conclusions: Our study emphasizes the importance of inflammation in the deregulation of glutamate homeostasis and provides a comprehensive mechanism of action for IL-1β-induced rod degeneration.

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Shaping of Signal Transmission at the Photoreceptor Synapse by EAAT2 Glutamate Transporters

Abstract: Visual Abstract

Cited by 25 publications

References 59 publications

Hexb enzyme deficiency leads to lysosomal abnormalities in radial glia and microglia in zebrafish brain development

Hexb enzyme deficiency leads to lysosomal abnormalities in radial glia and microglia in zebrafish brain development

Müller Glial Cells Participate in Retinal Waves via Glutamate Transporters and AMPA Receptors

IL-1β induces rod degeneration through the disruption of retinal glutamate homeostasis

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