Altered glutamate clearance in ascorbate deficient mice increases seizure susceptibility and contributes to cognitive impairment in APP/PSEN1 mice

Mi, Deborah J.; Dixit, Shilpy; Warner, Timothy A.; Kennard, John A.; Scharf, Daniel A.; Kessler, Eric Sean; Moore, Lisa Marie; Consoli, David C.; Bown, Corey W.; Eugene, Angeline J.; Kang, Jing‐Qiong; Harrison, Fiona E.

doi:10.1016/j.neurobiolaging.2018.08.002

Cited by 25 publications

(27 citation statements)

References 72 publications

(97 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This H 2 O 2 -associated suppression of glutamate uptake was due to direct oxidation of the sulfhydryl (SH) group of both transporter proteins [169]. In the same regard, a recent study in 2018 identified ascorbate (antioxidant secreted by astrocytes during glutamate clearance) as an essential antioxidant, protective against neuronal excitotoxicity [170]. In this study, ascorbate-deficient mice experienced behavioral changes and increased susceptibility to seizures compared to wild type (WT) mice.…”

Section: Glutamate Uptake In the Cnsmentioning

confidence: 99%

“…In this study, ascorbate-deficient mice experienced behavioral changes and increased susceptibility to seizures compared to wild type (WT) mice. This led the authors to conclude that low levels of antioxidants could explain the development of subclinical seizures associated with the cognitive impairment in patients with AD, who have a remarkably lower level of ascorbate in their CNS [170].…”

Section: Glutamate Uptake In the Cnsmentioning

confidence: 99%

See 1 more Smart Citation

Astrocytes Maintain Glutamate Homeostasis in the CNS by Controlling the Balance between Glutamate Uptake and Release

Mahmoud

Gharagozloo

Simard

et al. 2019

Cells

440

333

View full text Add to dashboard Cite

Glutamate is one of the most prevalent neurotransmitters released by excitatory neurons in the central nervous system (CNS); however, residual glutamate in the extracellular space is, potentially, neurotoxic. It is now well-established that one of the fundamental functions of astrocytes is to uptake most of the synaptically-released glutamate, which optimizes neuronal functions and prevents glutamate excitotoxicity. In the CNS, glutamate clearance is mediated by glutamate uptake transporters expressed, principally, by astrocytes. Interestingly, recent studies demonstrate that extracellular glutamate stimulates Ca2+ release from the astrocytes’ intracellular stores, which triggers glutamate release from astrocytes to the adjacent neurons, mostly by an exocytotic mechanism. This released glutamate is believed to coordinate neuronal firing and mediate their excitatory or inhibitory activity. Therefore, astrocytes contribute to glutamate homeostasis in the CNS, by maintaining the balance between their opposing functions of glutamate uptake and release. This dual function of astrocytes represents a potential therapeutic target for CNS diseases associated with glutamate excitotoxicity. In this regard, we summarize the molecular mechanisms of glutamate uptake and release, their regulation, and the significance of both processes in the CNS. Also, we review the main features of glutamate metabolism and glutamate excitotoxicity and its implication in CNS diseases.

show abstract

Section: Glutamate Uptake In the Cnsmentioning

confidence: 99%

Section: Glutamate Uptake In the Cnsmentioning

confidence: 99%

Astrocytes Maintain Glutamate Homeostasis in the CNS by Controlling the Balance between Glutamate Uptake and Release

Mahmoud

Gharagozloo

Simard

et al. 2019

Cells

440

333

View full text Add to dashboard Cite

show abstract

“…For example, postmortem investigation of patients with AD showed that GLT-1 was expressed more in activated astrocytes, and cognitive functions were preserved better before the patient’s death ( Kobayashi et al, 2018 ). Restoring GLT-1 expression by transgenic or pharmacological approaches in experimental animals significantly improved synaptic damage, Aβ deposition, and cognitive impairments ( Takahashi et al, 2015 ; Mi et al, 2018 ). This suggests that upregulation of GLT-1 expression and uptake for glutamate may be profitable for preserving cognition in AD patients or animal models.…”

Section: Discussionmentioning

confidence: 99%

GLT-1 Knockdown Inhibits Ceftriaxone-Mediated Improvements on Cognitive Deficits, and GLT-1 and xCT Expression and Activity in APP/PS1 AD Mice

Gao

Liu

et al. 2020

Front. Aging Neurosci.

View full text Add to dashboard Cite

Objective Glutamate transporter-1 (GLT-1) and system x c – mediate glutamate uptake and release, respectively. Ceftriaxone has been reported to upregulate GLT-1 expression and improve cognitive decline in APP/PS1 mice. The aim of the present study was to elucidate the role of GLT-1 in ceftriaxone-mediated improvement on cognitive deficits and associated changes in xCT (catalytic subunit of system x c – ) expression and activity using GLT-1 knockdown APP/PS1 mice. Methods GLT-1 knockdown (GLT-1 ± ) mice were generated in C57BL/6J mice using the CRISPR/Cas9 technique and crossed to APP/PS1 mice to generate GLT-1 ± APP/PS1 mice. The cognition was evaluated by novel object recognition and Morris water maze tests. GLT-1 and xCT expression, GLT-1 uptake for glutamate, and glutathione levels of hippocampus were assayed using Western blot and immunohistochemistry, 3 H-glutamate, and glutathione assay kit, respectively. Results In comparison with wild-type mice, APP/PS1 mice exhibited significant cognitive deficits, represented with poor performance in novel object recognition and Morris water maze tests, downregulated GLT-1 expression and glutamate uptake. Ceftriaxone treatment significantly improved the above impairments in APP/PS1 mice, but had negligible impact in GLT-1 ± APP/PS1 mice. The xCT expression increased in APP/PS1 and GLT-1 ± APP/PS1 mice. This upregulation might be a compensatory change against the accumulated glutamate resulting from GLT-1 impairment. Ceftriaxone treatment restored xCT expression in APP/PS1 mice, but not in GLT-1 ± APP/PS1 mice. Glutathione levels decreased in APP/PS1 mice in comparison to the wild-type group. After ceftriaxone administration, the decline in glutathione level was restored in APP/PS1 mice, but not in GLT-1 ± APP/PS1 mice. Conclusion Ceftriaxone improves cognitive impairment of APP/PS1 mice by upregulating GLT-1-mediated uptake of glutamate and co-regulation of GLT-1 and xCT in APP/PS1 mice.

show abstract

“…A concentration-dependent relationship between glutamate and ASC in striatum and hippocampal regions (cornu ammonis 1,3 (CA1,3) and dentate gyrus (DG)) has been shown in vivo in rats, highlighting a dynamic interplay between glutamate signaling and ASC fluctuation in the brain, with putative effects on behavioral responses [ 186 , 187 , 188 ]. Upon release, glutamate can be taken up by astrocytes, converted to glutamine and released for neuronal uptake [ 63 , 189 , 190 ]. The uptake of glutamate in astrocytes prompts ASC efflux possibly through induced cellular swelling and volume-sensitive anion channels, releasing ASC, e.g., to diminish glutamate-induced oxidative damage [ 60 , 63 ].…”

Section: Vitamin C Functions In the Brainmentioning

confidence: 99%

Vitamin C Deficiency in the Young Brain—Findings from Experimental Animal Models

Tveden‐Nyborg

2021

Nutrients

View full text Add to dashboard Cite

Severe and long-term vitamin C deficiency can lead to fatal scurvy, which is fortunately considered rare today. However, a moderate state of vitamin C (vitC) deficiency (hypovitaminosis C)—defined as a plasma concentration below 23 μM—is estimated to affect up to 10% of the population in the Western world, albeit clinical hallmarks in addition to scurvy have not been linked to vitC deficiency. The brain maintains a high vitC content and uniquely high levels during deficiency, supporting vitC’s importance in the brain. Actions include both antioxidant and co-factor functions, rendering vitamin C deficiency likely to affect several targets in the brain, and it could be particularly significant during development where a high cellular metabolism and an immature antioxidant system might increase sensitivity. However, investigations of a non-scorbutic state of vitC deficiency and effects on the developing young brain are scarce. This narrative review provides a comprehensive overview of the complex mechanisms that regulate vitC homeostasis in vivo and in the brain in particular. Functions of vitC in the brain and the potential consequences of deficiency during brain development are highlighted, based primarily on findings from experimental animal models. Perspectives for future investigations of vitC are outlined.

show abstract

Altered glutamate clearance in ascorbate deficient mice increases seizure susceptibility and contributes to cognitive impairment in APP/PSEN1 mice

Cited by 25 publications

References 72 publications

Astrocytes Maintain Glutamate Homeostasis in the CNS by Controlling the Balance between Glutamate Uptake and Release

Astrocytes Maintain Glutamate Homeostasis in the CNS by Controlling the Balance between Glutamate Uptake and Release

GLT-1 Knockdown Inhibits Ceftriaxone-Mediated Improvements on Cognitive Deficits, and GLT-1 and xCT Expression and Activity in APP/PS1 AD Mice

Vitamin C Deficiency in the Young Brain—Findings from Experimental Animal Models

Contact Info

Product

Resources

About