Differential regulation of the glutamate transporter variants GLT-1a and GLT-1b in the cortex and spinal cord of transgenic rats expressing hSOD1G93A

Dumont, Amélie; Hermans, Emmanuel; Goursaud, Stéphanie

doi:10.1016/j.neuint.2013.04.012

Cited by 11 publications

(7 citation statements)

References 56 publications

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“…This study provides evidence that ALS increases the expression of the ABCC8 and KCNJ8 genes in the spinal cord and KCNJ11 in the motor cortex of patients. Moreover, we report for the first time on the association of the rs4148646 G/G and rs5219 T/T variants of the ABCC8 and KCNJ11 genes respectively with longer survival times in bulbar ALS; and on the association of the rs4148642 C/C and rs148416760 T/C variants of the described for genes such as human sirtuins [46], a protein family involved in the control of neuroinflammation [47], and rat glutamate transporter 1 variants [48]. These tissuedependent variations in gene expression have been proposed to explain in some extent susceptibility of tissues to cell loss and to modify ALS progression [48].…”

Section: Discussionmentioning

confidence: 78%

KATP Channel Expression and Genetic Polymorphisms Associated with Progression and Survival in Amyotrophic Lateral Sclerosis

et al. 2018

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The ATP-sensitive potassium (K) channel directly regulates the microglia-mediated inflammatory response following CNS injury. To determine the putative role of the K channel in amyotrophic lateral sclerosis (ALS) pathology, we investigated whether ALS induces changes in K channel expression in the spinal cord and motor cortex. We also characterized new functional variants of human ABCC8, ABCC9, KCNJ8, and KCNJ11 genes encoding for the K channel and analyzed their association with ALS risk, rate of progression, and survival in a Spanish ALS cohort. The expression of ABCC8 and KCNJ8 genes was enhanced in the spinal cord of ALS samples, and KCNJ11 increased in motor cortex of ALS samples, as determined by real-time polymerase chain reaction. We then sequenced the exons and regulatory regions of K channel genes from a subset of 28 ALS patients and identified 50 new genetic variants. For the case-control association analysis, we genotyped five selected polymorphisms with predicted functional relevance in 185 Spanish ALS (134 spinal ALS and 51 bulbar ALS) patients and 493 controls. We found that bulbar ALS patients presenting the G/G genotype of the rs4148646 variant of ABCC8 and the T/T genotype of the rs5219 variant of KCNJ11 survived longer than other ALS patients presenting other genotypes. Also, the C/C genotype of the rs4148642 variant of ABCC8 and the T/C genotype of the rs148416760 variant of ABCC9 modified the progression rate in spinal ALS patients. Our results suggest that the K channel plays a role in the pathophysiological mechanisms of ALS.

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Section: Discussionmentioning

confidence: 78%

KATP Channel Expression and Genetic Polymorphisms Associated with Progression and Survival in Amyotrophic Lateral Sclerosis

et al. 2018

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“…14,15 Recent studies have reported abnormalities in cortical motor neurons in SOD1-G93A mice and rats. 6,[16][17][18] We reported that tongue force training increases excitability of oromotor cortical regions in healthy rats. 19 Glutamate regulation is impaired in animal models of ALS as well as in both familial and sporadic forms of human ALS.…”

Section: Discussionmentioning

confidence: 95%

“…Muscle weakness, atrophy and hyporeflexia are signs of lower motor neuron involvement, while speed of repetitive voluntary movements reflects upper motor neuron integrity 14,15 . Recent studies have reported abnormalities in cortical motor neurons in SOD1-G93A mice and rats 6,16,17,18 . We reported that tongue force training increases excitability of oromotor cortical regions in healthy rats 19 .…”

Section: Discussionmentioning

confidence: 99%

Effects of Tongue Force Training on Bulbar Motor Function in the Female SOD1-G93A Rat Model of Amyotrophic Lateral Sclerosis

Shuler

Kumar

et al. 2016

Neurorehabil Neural Repair

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Background The use of exercise in Amyotrophic Lateral Sclerosis (ALS) is controversial. Although moderate exercise appears to be beneficial for limb muscles in ALS, the effects of exercise on bulbar muscles such as the tongue have not been studied. Objective The aim of this study was to determine the effects of tongue force training on bulbar motor function in the SOD1-G93A rat model of ALS. Methods We compared the effects of tongue force training on bulbar motor function and neuromuscular junction (NMJ) innervation in female SOD1-G93A rats and age-matched female wild-type controls. Half of each group underwent afternoon tongue force training sessions, while all rats were tested under minimal force conditions in the mornings. Results Tongue force did not differ between the SOD1-G93A rats and healthy controls during the morning testing sessions, nor was it affected by training. Surprisingly, decreases in tongue motility, the number of licks per session, and body weight were greater in the tongue force-trained SOD1-G93A rats. Forelimb grip force, survival, and denervation of the genioglossus muscle did not differ between the trained and untrained SOD1-G93A rats. Genioglossus innervation was correlated with changes in tongue force but not tongue motility in SOD1-G93A rats at end stage. Conclusions The results indicate a potential deleterious effect of tongue force training on tongue motility in female SOD1-G93A rats. The lack of relationship between genioglossus innervation and tongue motility suggest that factors other than lower motor neuron integrity likely accounted for this effect.

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“…The loss of function of EAAT2 during ALS has also been demonstrated experimentally on different levels: in an ALS rat model with SOD-1 mutation, glutamate transport was impaired [113] and EAAT2 expression was diminished [114]. In several studies performed in SOD-1 mutated mice, a reduced expression of EAAT2 in the spinal ccord was observed [115][116][117][118][119]. EAAT1, however, was not changed over the course of the disease in the motor cortex from ALS patients or in transgenic rats expressing the human SOD-1 mutant G93A [112,119].…”

Section: Amyotrophic Lateral Sclerosismentioning

confidence: 90%

Glial Glutamate Transporter-Mediated Plasticity: System xc-/xCT/SLC7A11 and EAAT1/2 in Brain Diseases

Dahlmanns¹,

Dahlmanns²,

Savaskan³

et al. 2023

Front. Biosci. (Landmark Ed)

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Glial cells play an essential role in the complex function of the nervous system. In particular, astrocytes provide nutritive support for neuronal cells and are involved in regulating synaptic transmission. Oligodendrocytes ensheath axons and support information transfer over long distances. Microglial cells constitute part of the innate immune system in the brain. Glial cells are equipped with the glutamatecystine-exchanger xCT (SLC7A11), the catalytic subunit of system xc − , and the excitatory amino acid transporter 1 (EAAT1, GLAST) and EAAT2 (GLT-1). Thereby, glial cells maintain balanced extracellular glutamate levels that enable synaptic transmission and prevent excitotoxic states. Expression levels of these transporters, however, are not fixed. Instead, expression of glial glutamate transporters are highly regulated in reaction to the external situations. Interestingly, such regulation and homeostasis is lost in diseases such as glioma, (tumor-associated) epilepsy, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis or multiple sclerosis. Upregulation of system xc − (xCT or SLC7A11) increases glutamate export from the cell, while a downregulation of EAATs decreases intracellular glutamate import. Occurring simultaneously, these reactions entail excitotoxicity and thus harm neuronal function. The release of glutamate via the antiporter system xc − is accompanied by the import of cystine-an amino acid essential in the antioxidant glutathione. This homeostasis between excitotoxicity and intracellular antioxidant response is plastic and off-balance in central nervous system (CNS) diseases. System xc − is highly expressed on glioma cells and sensitizes them to ferroptotic cell death. Hence, system xc − is a potential target for chemotherapeutic add-on therapy. Recent research reveals a pivotal role of system xc − and EAAT1/2 in tumor-associated and other types of epilepsy. Numerous studies show that in Alzheimer's disease, amyotrophic lateral sclerosis and Parkinson's disease, these glutamate transporters are dysregulated-and disease mechanisms could be interposed by targeting system xc − and EAAT1/2. Interestingly, in neuroinflammatory diseases such as multiple sclerosis, there is growing evidence for glutamate transporter involvement. Here, we propose that the current knowledge strongly suggest a benefit from rebalancing glial transporters during treatment.

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Differential regulation of the glutamate transporter variants GLT-1a and GLT-1b in the cortex and spinal cord of transgenic rats expressing hSOD1G93A

Cited by 11 publications

References 56 publications

KATP Channel Expression and Genetic Polymorphisms Associated with Progression and Survival in Amyotrophic Lateral Sclerosis

KATP Channel Expression and Genetic Polymorphisms Associated with Progression and Survival in Amyotrophic Lateral Sclerosis

Effects of Tongue Force Training on Bulbar Motor Function in the Female SOD1-G93A Rat Model of Amyotrophic Lateral Sclerosis

Glial Glutamate Transporter-Mediated Plasticity: System xc-/xCT/SLC7A11 and EAAT1/2 in Brain Diseases

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