Hyperexcitability and brain morphological differences in mice lacking the cystine/glutamate antiporter, system x<sub>c</sub><sup>−</sup>

Sears, Sheila M. S.; Roberts, Sarah H.; Hewett, Sandra J.

doi:10.1002/jnr.24971

Cited by 6 publications

(9 citation statements)

References 70 publications

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“…The current manuscript reports on the first elaborate study of the effects of system x c − deficiency on the aging process of male mice, while gender differences have been reported both in the age-related changes in the immune response, in age-related frailty and cognitive impairment (for review [ 90 ]), and in the reaction of the brain to genetic xCT deletion [ 91 , 92 ]. Our conclusions also rely on observations in a single transgenic mouse model with a genetic deletion of xCT [ 6 ].…”

Section: Discussionmentioning

confidence: 99%

“…This strain carries a large spontaneous mutation that includes -but also extends beyond- exon 12 of the xCT-encoding gene [ 44 , 93 ]. Although some findings on hippocampal and cognitive function that have been reported in the sut mice [ 94 – 96 ] are conflicting with those in the xCT −/− mice, these discrepancies seem absent when comparing the sut mice with littermate controls [ 91 , 92 ]. Still, it would be of interest to confirm the major findings of the current study both in female mice and by using different strategies to target system x c − .…”

Section: Discussionmentioning

confidence: 99%

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Lifespan extension with preservation of hippocampal function in aged system xc−-deficient male mice

et al. 2022

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The cystine/glutamate antiporter system xc− has been identified as the major source of extracellular glutamate in several brain regions as well as a modulator of neuroinflammation, and genetic deletion of its specific subunit xCT (xCT−/−) is protective in mouse models for age-related neurological disorders. However, the previously observed oxidative shift in the plasma cystine/cysteine ratio of adult xCT−/− mice led to the hypothesis that system xc− deletion would negatively affect life- and healthspan. Still, till now the role of system xc− in physiological aging remains unexplored. We therefore studied the effect of xCT deletion on the aging process of mice, with a particular focus on the immune system, hippocampal function, and cognitive aging. We observed that male xCT−/− mice have an extended lifespan, despite an even more increased plasma cystine/cysteine ratio in aged compared to adult mice. This oxidative shift does not negatively impact the general health status of the mice. On the contrary, the age-related priming of the innate immune system, that manifested as increased LPS-induced cytokine levels and hypothermia in xCT+/+ mice, was attenuated in xCT−/− mice. While this was associated with only a very moderate shift towards a more anti-inflammatory state of the aged hippocampus, we observed changes in the hippocampal metabolome that were associated with a preserved hippocampal function and the retention of hippocampus-dependent memory in male aged xCT−/− mice. Targeting system xc− is thus not only a promising strategy to prevent cognitive decline, but also to promote healthy aging.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Lifespan extension with preservation of hippocampal function in aged system xc−-deficient male mice

et al. 2022

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“…In line with this, system x c − null mice (xCT sut/sut ) displayed a reduced occurrence of seizures in a pentylenetetrazole kindling model, a model in which inhibition of GABA A receptors increases synaptic stimulation and excitation [83,84]. Although the same authors, however, later reported lower seizure thresholds in system x c − null mice after kainic acid or pentylenetetrazole and more severe seizures [85]-ascribing a seizure-preventing role to system x c − -it generally appears that targeting glial system x c − may support therapy of seizures. In a very recent study, the system x c − inhibitor sulfasalazine could ameliorate seizures that were elicited by astrogliosis [86], ruling out pharmacological manipulations that potentially may occur during seizure induction.…”

Section: System X C − and Eaat1/2 In Peritumoral Astrocytes And Their...mentioning

confidence: 64%

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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“…Bushy shape (in vivo) Unipolar or bipolar shape (Doetsch et al, 1999b;Fedoroff and Vernadakis, 1986 ( Lalo et al, 2006;Liu et al, 2006;Nwaobi et al, 2016) ADK positive ADK expressed at low levels Regulates adenosine homeostasis in the CNS (Beckervordersandforth et al, 2010;Dulken et al, 2017) SLC7A11 (cystine-glutamate antiporter, system X(c)) positive SLC7A11 expressed at low levels Sodium-independent channel transports cysteine in exchange for glutamate to maintain extracellular glutamate levels (Beckervordersandforth et al, 2010;Bender et al, 2000;Dulken et al, 2017;Sears et al, 2021) CD9 (tetraspanin) high CD9 low Cell surface glycoprotein that binds to integrins to influence cell interactions. Regulates outgrowth of astrocytic processes (Llorens-Bobadilla et al, 2015;Schmidt et al, 1996) Low levels of nucleostemin (GNL3)…”

Section: Svz Nscs Citationsmentioning

confidence: 99%

Neural Stem Cells in Adult Mammals are not Astrocytes

et al. 2022

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At the turn of the 21st century studies of the cells that resided in the adult mammalian subventricular zone (SVZ) characterized the neural stem cells (NSCs) as a subtype of astrocyte. Over the ensuing years, numerous studies have further characterized the properties of these NSCs and compared them to parenchymal astrocytes. Here we have evaluated the evidence collected to date to establish whether classifying the NSCs as astrocytes is appropriate and useful. We also performed a meta-analysis with 4 previously published datasets that used cell sorting and unbiased single-cell RNAseq to highlight the distinct gene expression profiles of adult murine NSCs and niche astrocytes. On the basis of our understanding of the properties and functions of astrocytes versus the properties and functions of NSCs, and from our comparative transcriptomic analyses we conclude that classifying the adult mammalian NSC as an astrocyte is potentially misleading. From our vantage point, it is more appropriate to refer to the cells in the adult mammalian SVZ that retain the capacity to produce new neurons and macroglia as NSCs without attaching the term “astrocyte-like.”

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Hyperexcitability and brain morphological differences in mice lacking the cystine/glutamate antiporter, system x_c⁻

Cited by 6 publications

References 70 publications

Lifespan extension with preservation of hippocampal function in aged system xc−-deficient male mice

Lifespan extension with preservation of hippocampal function in aged system xc−-deficient male mice

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

Neural Stem Cells in Adult Mammals are not Astrocytes

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Hyperexcitability and brain morphological differences in mice lacking the cystine/glutamate antiporter, system xc−

Cited by 6 publications

References 70 publications

Lifespan extension with preservation of hippocampal function in aged system xc−-deficient male mice

Lifespan extension with preservation of hippocampal function in aged system xc−-deficient male mice

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

Neural Stem Cells in Adult Mammals are not Astrocytes

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Hyperexcitability and brain morphological differences in mice lacking the cystine/glutamate antiporter, system x_c⁻