A Computational Study of Astrocytic GABA Release at the Glutamatergic Synapse: EAAT-2 and GAT-3 Coupled Dynamics

Flanagan, Bronac; McDaid, Liam; Wade, John; Toman, Marinus; Wong‐Lin, KongFatt; Harkin, Jim

doi:10.3389/fncel.2021.682460

Cited by 5 publications

(3 citation statements)

References 45 publications

(69 reference statements)

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“…Astroglial GABA release through Best1 mediates GABA tone in the thalamus and permits tactile discrimination in mice [87]. Additionally, the increases in intracellular Na + in astrocytes arising from glutamate transport can lead to extrusion of GABA via reversal of GAT transport [88][89][90][91].…”

Section: Astrocyte Regulation Of Inhibitory Synapsesmentioning

confidence: 99%

Astrocyte regulation of synaptic signaling in psychiatric disorders

Kruyer¹,

Kalivas²,

Scofield³

2022

Neuropsychopharmacol.

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Over the last 15 years, the field of neuroscience has evolved toward recognizing the critical role of astroglia in shaping neuronal synaptic activity and along with the pre-and postsynapse is now considered an equal partner in tripartite synaptic transmission and plasticity. The relative youth of this recognition and a corresponding deficit in reagents and technologies for quantifying and manipulating astroglia relative to neurons continues to hamper advances in understanding tripartite synaptic physiology. Nonetheless, substantial advances have been made and are reviewed herein. We review the role of astroglia in synaptic function and regulation of behavior with an eye on how tripartite synapses figure into brain pathologies underlying behavioral impairments in psychiatric disorders, both from the perspective of measures in postmortem human brains and more subtle influences on tripartite synaptic regulation of behavior in animal models of psychiatric symptoms. Our goal is to provide the reader a wellreferenced state-of-the-art understanding of current knowledge and predict what we may discover with deeper investigation of tripartite synapses using reagents and technologies not yet available.

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Section: Astrocyte Regulation Of Inhibitory Synapsesmentioning

confidence: 99%

Astrocyte regulation of synaptic signaling in psychiatric disorders

Kruyer¹,

Kalivas²,

Scofield³

2022

Neuropsychopharmacol.

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“…While an NMDA receptor antagonist blocked the FC-mediated facilitation of LTD, it is possible that activation of NMDA receptors promotes the increase in dopamine levels or that a concomitant activation is required, but further experiments are needed to outline this interaction. Lastly, astrocytes may regulate both glutamatergic and dopaminergic neurotransmission through the uptake and release of GABA [ 87 , 88 , 89 , 90 , 91 , 92 ]. While FC-mediated synaptic depression in the striatum is independent of GABA A -receptor activation [ 39 ], GABAergic neurotransmission may still play a role in the facilitation of HFS-LTD.…”

Section: Discussionmentioning

confidence: 99%

Astrocytic Regulation of Endocannabinoid-Dependent Synaptic Plasticity in the Dorsolateral Striatum

Adermark,

Stomberg,

Söderpalm

et al. 2024

IJMS

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Astrocytes are pivotal for synaptic transmission and may also play a role in the induction and expression of synaptic plasticity, including endocannabinoid-mediated long-term depression (eCB-LTD). In the dorsolateral striatum (DLS), eCB signaling plays a major role in balancing excitation and inhibition and promoting habitual learning. The aim of this study was to outline the role of astrocytes in regulating eCB signaling in the DLS. To this end, we employed electrophysiological slice recordings combined with metabolic, chemogenetic and pharmacological approaches in an attempt to selectively suppress astrocyte function. High-frequency stimulation induced eCB-mediated LTD (HFS-LTD) in brain slices from both male and female rats. The metabolic uncoupler fluorocitrate (FC) reduced the probability of transmitter release and depressed synaptic output in a manner that was independent on cannabinoid 1 receptor (CB1R) activation. Fluorocitrate did not affect the LTD induced by the CB1R agonist WIN55,212-2, but enhanced CB1R-dependent HFS-LTD. Reduced neurotransmission and facilitated HFS-LTD were also observed during chemogenetic manipulation using Gi-coupled DREADDs targeting glial fibrillary acidic protein (GFAP)-expressing cells, during the pharmacological inhibition of connexins using carbenoxolone disodium, or during astrocytic glutamate uptake using TFB-TBOA. While pretreatment with the N-methyl-D-aspartate (NMDA) receptor antagonist 2-amino-5-phosphonopentanoic acid (APV) failed to prevent synaptic depression induced by FC, it blocked the facilitation of HFS-LTD. While the lack of tools to disentangle astrocytes from neurons is a major limitation of this study, our data collectively support a role for astrocytes in modulating basal neurotransmission and eCB-mediated synaptic plasticity.

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“…9). Although enhanced uptake is a noncanonical dysfunction, it can lead to loss of neuronal plasticity [63,97,124,125]. Studies show that increased intracellular glutamate alters the gradient and homeostatic balance, leading to astrocyte dysfunction and decreasing EAAT-1/2 sensitivity towards glutamate, ultimately leading to reduced uptake and excitotoxicity [124].…”

Section: Discussionmentioning

confidence: 99%

HIV Nef Expression Down-modulated GFAP Expression and Altered Glutamate Uptake and Release and Proliferation in Astrocytes

Wilson¹,

He²

2023

Aging and disease

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HIV infection of astrocytes leads to restricted gene expression and replication but abundant expression of HIV early genes Tat, Nef and Rev. A great deal of neuroHIV research has so far been focused on Tat protein, its effects on astrocytes, and its roles in neuroHIV. In the current study, we aimed to determine effects of Nef expression on astrocytes and their function. Using transfection or infection of VSVG-pseudotyped HIV viruses, we showed that Nef expression down-modulated glial fibrillary acidic protein (GFAP) expression. We then showed that Nef expression also led to decreased GFAP mRNA expression. The transcriptional regulation was further confirmed using a GFAP promoter-driven reporter gene assay. We performed transcription factor profiling array to compare the expression of transcription factors between Nef-intact and Nef-deficient HIV-infected cells and identified eight transcription factors with expression changes of 1.5-fold or higher: three up-regulated by Nef (Stat1, Stat5, and TFIID), and five down-regulated by Nef (AR, GAS/ISRE, HIF, Sp1, and p53). We then demonstrated that removal of the Sp1 binding sites from the GFAP promoter resulted in a much lower level of the promoter activity and reversal of Nef effects on the GFAP promoter, confirming important roles of Sp1 in the GFAP promoter activity and for Nef-induced GFAP expression. Lastly, we showed that Nef expression led to increased glutamate uptake and decreased glutamate release by astrocytes and increased astrocyte proliferation. Taken together, these results indicate that Nef leads to down-modulation of GFAP expression and alteration of glutamate metabolism in astrocytes, and astrocyte proliferation and could be an important contributor to neuroHIV.

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A Computational Study of Astrocytic GABA Release at the Glutamatergic Synapse: EAAT-2 and GAT-3 Coupled Dynamics

Cited by 5 publications

References 45 publications

Astrocyte regulation of synaptic signaling in psychiatric disorders

Astrocyte regulation of synaptic signaling in psychiatric disorders

Astrocytic Regulation of Endocannabinoid-Dependent Synaptic Plasticity in the Dorsolateral Striatum

HIV Nef Expression Down-modulated GFAP Expression and Altered Glutamate Uptake and Release and Proliferation in Astrocytes

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