Astrocytic Regulation of Glutamate Transmission in Schizophrenia

Mei, Yu-Ying; Wu, Dong; Zhou, Ning

doi:10.3389/fpsyt.2018.00544

Cited by 41 publications

(54 citation statements)

References 115 publications

(133 reference statements)

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“…Network analysis also affirmed the association of gene expression changes in the glial CGs to SCZ. Ubiquitous transcriptional dysregulation in glial CGs and changes in their proportions are consistent with previous findings involving glial cells in the onset of SCZ, as related to the involvement of synaptic transduction 49 , inflammation 50 , and myelination 51 . Whether and how alterations of glial cells interact with neurons and circuits would be an important question for future studies.…”

Section: Discussionsupporting

confidence: 91%

Cell group analysis reveals changes in upper-layer neurons associated with schizophrenia

Dai

Chen

Liu

et al. 2020

Preprint

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Genome-wide association studies (GWAS) of schizophrenia (SCZ) have revealed over 100 risk loci. We investigated whether these SCZ-associated variants regulate gene expression by cell type. Using a fully unsupervised deconvolution method, we calculated gene expression by clusters of estimated cell types (cell-groups, CGs). Five CGs emerged in the dorsolateral prefrontal cortices (DLPFC) of 341 donors with and without SCZ. By mapping expression quantitative trait loci (eQTL) per CG, we partitioned the CG-specific heritability of SCZ risk in GWAS. CG-specific expressions and eQTLs were replicated in another independent deconvoluted bulk tissue data and single-cell expression data. Further, we characterized CG-specific gene differential expression and cell proportion changes in SCZ brains. We found upper-layer neurons in the DLPFC to be associated with SCZ based on enrichment of risk heritability in eQTLs, disease-related transcriptional signatures and cell type disproportion. Our study suggests that neurons and related anomalous circuits in upper layers of the DLPFC may have a major contribution to SCZ risk.

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Section: Discussionsupporting

confidence: 91%

Cell group analysis reveals changes in upper-layer neurons associated with schizophrenia

Dai

Chen

Liu

et al. 2020

Preprint

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“…Mice with reduced EAAT1 levels also showed cognitive symptoms. The lack of EAAT1 makes the cells more sensitive to various traumatic factors (Mei et al, 2018).…”

Section: Glutamate Systemmentioning

confidence: 99%

“…Haloperidol and clozapine reduce GLT-1 and EAAT3 levels in rodents, while aripiprazole reduces EAAT1 expression but has minimal effect on GLT-1, which may further lead to differences in effects on positive, negative, and cognitive symptoms (Segnitz et al, 2009;Mei et al, 2018).…”

Section: Glutamate Systemmentioning

confidence: 99%

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Alterations of Astrocytes in the Context of Schizophrenic Dementia

et al. 2020

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The levels of the astrocyte markers (GFAP, S100B) were increased unevenly in patients with schizophrenia. Reactive astrogliosis was found in approximately 70% of patients with schizophrenia. The astrocytes play a major role in etiology and pathogenesis of schizophrenia. Astrocytes produce the components that altered in schizophrenia extracellular matrix system which are involved in inflammation, functioning of interneurons, glio-, and neurotransmitter system, especially glutamate system. Astrocytes activate the interneurons through glutamate release and ATP. Decreased expression of astrocyte glutamate transporters was observed in patients with schizophrenia. Astrocytes influence on N-methyl-d-aspartate (NMDA) receptors via Dserine, an agonist of the glycine-binding site of NMDA receptors, and kynurenic acid, an endogenous antagonist. NMDA receptors, on its turn, control the impulses of dopamine neurons. Therefore following theories of schizophrenia are proposed. They are a) activation of astrocytes for neuroinflammation, b) glutamate and dopamine theory, as astrocyte products control the activity of NMDA receptors, which influence on the dopamine neurons.

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“…Second, KBs are the preferred oxidative substrate for "powering" the glutamate-glutamine cycle in the environment of cerebral glucose hypometabolism seen in neurodegenerative and neuroprogressive disorders [201]. Third, and perhaps expectedly, evidence of dysfunction or dysregulation of this cycle is present in at least some regions of the brain in patients with SZ [202], MDD [203], BPD [204], AD [205], HD [206], ALS [207], and PD [208]. Moreover, impairment of this cycle is a major element in the development of disturbed glutamate homeostasis, with glutamate excitotoxicity, and reduced GABAergic signaling, which play a causative role in the pathogenesis of most if not all neurodegenerative and neuroprogressive conditions [209,210].…”

Section: Effect Of Nutritional Ketosis On the Astrocyte Glutamate-glumentioning

confidence: 99%

Nutritional ketosis as an intervention to relieve astrogliosis: Possible therapeutic applications in the treatment of neurodegenerative and neuroprogressive disorders

et al. 2020

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Nutritional ketosis, induced via either the classical ketogenic diet or the use of emulsified medium-chain triglycerides, is an established treatment for pharmaceutical resistant epilepsy in children and more recently in adults. In addition, the use of oral ketogenic compounds, fractionated coconut oil, very low carbohydrate intake, or ketone monoester supplementation has been reported to be potentially helpful in mild cognitive impairment, Parkinson’s disease, schizophrenia, bipolar disorder, and autistic spectrum disorder. In these and other neurodegenerative and neuroprogressive disorders, there are detrimental effects of oxidative stress, mitochondrial dysfunction, and neuroinflammation on neuronal function. However, they also adversely impact on neurone–glia interactions, disrupting the role of microglia and astrocytes in central nervous system (CNS) homeostasis. Astrocytes are the main site of CNS fatty acid oxidation; the resulting ketone bodies constitute an important source of oxidative fuel for neurones in an environment of glucose restriction. Importantly, the lactate shuttle between astrocytes and neurones is dependent on glycogenolysis and glycolysis, resulting from the fact that the astrocytic filopodia responsible for lactate release are too narrow to accommodate mitochondria. The entry into the CNS of ketone bodies and fatty acids, as a result of nutritional ketosis, has effects on the astrocytic glutamate–glutamine cycle, glutamate synthase activity, and on the function of vesicular glutamate transporters, EAAT, Na+, K+-ATPase, Kir4.1, aquaporin-4, Cx34 and KATP channels, as well as on astrogliosis. These mechanisms are detailed and it is suggested that they would tend to mitigate the changes seen in many neurodegenerative and neuroprogressive disorders. Hence, it is hypothesized that nutritional ketosis may have therapeutic applications in such disorders.

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Astrocytic Regulation of Glutamate Transmission in Schizophrenia

Cited by 41 publications

References 115 publications

Cell group analysis reveals changes in upper-layer neurons associated with schizophrenia

Cell group analysis reveals changes in upper-layer neurons associated with schizophrenia

Alterations of Astrocytes in the Context of Schizophrenic Dementia

Nutritional ketosis as an intervention to relieve astrogliosis: Possible therapeutic applications in the treatment of neurodegenerative and neuroprogressive disorders

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