Thyroid hormone increases astrocytic glutamate uptake and protects astrocytes and neurons against glutamate toxicity

Mendes-de-Aguiar, Cláudia Beatriz Nedel; Alchini, Ricardo; Decker, Helena; Alvarez-Silva, Márcio; Tasca, Carla I.; Trentin, Andréa Gonçalves

doi:10.1002/jnr.21755

Cited by 88 publications

(65 citation statements)

References 49 publications

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“…It is well-known that reactive astrocytes develop some characteristics of immature cells, such as the expression of vimentin and BLBP484950515253545556. In addition, BR1 and H9 astrocytes stained for rNMDA and GLT1, which are specific for mature astrocytes5758.…”

Section: Discussionmentioning

confidence: 99%

Derivation of Functional Human Astrocytes from Cerebral Organoids

Dezonne

Sartore

Nascimento

et al. 2017

Sci Rep

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Astrocytes play a critical role in the development and homeostasis of the central nervous system (CNS). Astrocyte dysfunction results in several neurological and degenerative diseases. However, a major challenge to our understanding of astrocyte physiology and pathology is the restriction of studies to animal models, human post-mortem brain tissues, or samples obtained from invasive surgical procedures. Here, we report a protocol to generate human functional astrocytes from cerebral organoids derived from human pluripotent stem cells. The cellular isolation of cerebral organoids yielded cells that were morphologically and functionally like astrocytes. Immunolabelling and proteomic assays revealed that human organoid-derived astrocytes express the main astrocytic molecular markers, including glutamate transporters, specific enzymes and cytoskeletal proteins. We found that organoid-derived astrocytes strongly supported neuronal survival and neurite outgrowth and responded to ATP through transient calcium wave elevations, which are hallmarks of astrocyte physiology. Additionally, these astrocytes presented similar functional pathways to those isolated from adult human cortex by surgical procedures. This is the first study to provide proteomic and functional analyses of astrocytes isolated from human cerebral organoids. The isolation of these astrocytes holds great potential for the investigation of developmental and evolutionary features of the human brain and provides a useful approach to drug screening and neurodegenerative disease modelling.

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Section: Discussionmentioning

confidence: 99%

Derivation of Functional Human Astrocytes from Cerebral Organoids

Dezonne

Sartore

Nascimento

et al. 2017

Sci Rep

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“…64,65) T3 enhances the expression levels of astrocytic glutamate transporters (GLAST and GLT-1). 66) Furthermore, thyroid hormones indirectly affect neuronal differentiation and function through their action in astrocytes. For example, it has been observed that T3-primed astrocytes express higher levels of heparan sulfate proteoglycans, which provide neurite outgrowth effects.…”

Section: Organic Anion Transportersmentioning

confidence: 99%

Functional Expression of Organic Ion Transporters in Astrocytes and Their Potential as a Drug Target in the Treatment of Central Nervous System Diseases

Furihata

Anzai

2017

Biological & Pharmaceutical Bulletin

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It has become widely acknowledged that astrocytes play essential roles in maintaining physiological central nervous system (CNS) activities. Astrocytes fulfill their roles partly through the manipulation of their plasma membrane transporter functions, and therefore these transporters have been regarded as promising drug targets for various CNS diseases. A representative example is excitatory amino acid transporter 2 (EAAT2), which works as a critical regulator of excitatory signal transduction through its glutamate uptake activity at the tripartite synapse. Thus, enhancement of EAAT2 functionality is expected to accelerate glutamate clearance at synapses, which is a promising approach for the prevention of over-excitation of glutamate receptors. In addition to such well-known astrocyte-specific transporters, cumulative evidence suggests that multi-specific organic ion transporters (i.e., organic cation/anion transporters [OCTs/OATs], carnitine/organic cation transporters [OCTNs], and organic anion transporting polypeptides [OATPs]) are also functionally expressed in astrocytes. Even though identification and characterization of their physiological/pathophysiological roles in astrocytes are in the initial stage, the findings obtained so far indicate that OCT3 and plasma membrane monoamine transporter are significantly involved in the clearance of biogenic amine neurotransmitters in the synaptic cleft, and that OCTN2 and OATP1C1 provide a cellular entry gate for carnitine/acetyl-L-carnitine and thyroxine, respectively. Therefore, organic ion transporters, including those mentioned above, are expected to become emerging pharmacological targets for various CNS diseases. With such expectations in mind, this review will briefly summarize the functional expression of organic ion transporters in astrocytes.

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“…A study of rats showed that astrocytes treated with T3 increased mRNA levels and protein expression of the glutamate transporters, glutamate aspartate transporter (GLAST) and glial glutamate transporter-1 (GLT1). This ultimately regulated the extracellular glutamate content [11]. Some studies have shown that autoimmune thyroiditis and type 1 diabetes mellitus (T1DM) used the same antibody as glutamic acid decarboxylase antibodies (GAD-Ab).…”

Section: Discussionmentioning

confidence: 99%