Downregulation of glial glutamate transporters after dopamine denervation in the striatum of 6‐hydroxydopamine‐lesioned rats

Chung, Elaine K.Y.; Chen, L. W.; Chan, Ying-Shing; Yung, Kin Lam

doi:10.1002/cne.21852

Cited by 86 publications

(79 citation statements)

References 79 publications

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“…A similar upregulation of GFAP has been shown in 6-OHDA-or MPTP-lesion models in which the neurotoxins are injected directly into the striatum (Chadi and Gomide 2004;Gomide et al 2005;Henning et al 2008;Yoo et al 2005), the median forebrain bundle (Henning et al 2008;Stromberg et al 1986), or the substantia nigra (Chung et al 2008;Sheng et al 1993). Similar to our findings, the activation of astrocytes in these studies is not restricted to the direct sites of 6-OHDA or MPTP injection but comprise various brain regions (Chadi and Gomide 2004;Gomide et al 2005) that represent target areas of dopaminergic projections.…”

Section: Discussionmentioning

confidence: 78%

“…The injection of the neurotoxin 6-OHDA into the nigrostriatal system can be used to study the effect of dopaminergic depletion not only on neurons or neuronal precursors (Aponso et al 2008;Chung et al 2008;Hoglinger et al 2004;Hu et al 1990;Rodriguez et al 2001), but also on astrocytes (Gordon et al 1997;Henning et al 2008;Sheng et al 1993;Stromberg et al 1986;Yoo et al 2005). We have investigated the effect of 6-OHDA on astrocytes in the striatum and cortex in the adult rat brain, in a model in which the neurotoxin is not injected into the nigro-striatal system but into the lateral ventricles.…”

Section: Discussionmentioning

confidence: 99%

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Effect of 6-hydroxydopamine (6-OHDA) on proliferation of glial cells in the rat cortex and striatum: evidence for de-differentiation of resident astrocytes

et al. 2010

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Reactive astrogliosis is the universal response to any brain insult. It is characterized by cellular hypertrophy, up-regulation of the astrocyte marker glial fibrillary acidic protein (GFAP), and proliferation. The source of these proliferating cells is under intense debate. Progenitor cells derived from the subventricular zone (SVZ), cells positive for chondroitin sulfate proteoglycan (NG2(+)), and de-differentiated astrocytes have been proposed as the origin of proliferating cells following injury. We have analyzed the effect of intraventricular-applied 6-hydroxydopamine (6-OHDA) on the proliferation and morphology of astrocytes in rat cortex and striatum by means of immunohistochemistry and confocal laser microscopy. At 4 days post-lesion, GFAP expression increased markedly. A subpopulation of the GFAP(+) cells co-expressed Ki-67, indicating that these cells were proliferating. To investigate whether these cells (1) arose from migrating SVZ progenitor cells, (2) derived from NG2(+) progenitor cells, or (3) de-differentiated from resident astrocytes, we studied the expression of the migration marker doublecortin (Dcx), the oligodendrocyte progenitor marker NG2, and the progenitor markers Nestin and Pax6. The proliferating Ki-67(+) cells co-expressed Nestin and Pax6, whereas no co-expression of Ki-67 with NG2 or the migration marker Dcx was observed. Thus, resident astrocytes de-differentiate, in response to the intraventricular application of 6-OHDA, to a phenotype resembling radial glia cells, which represent transient astrocyte precursors during development. An understanding of the mechanisms of the de-differentiation of mature astrocytes might be useful for designing new approaches to cell therapy in neurodegenerative diseases such as Parkinson's disease.

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Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Effect of 6-hydroxydopamine (6-OHDA) on proliferation of glial cells in the rat cortex and striatum: evidence for de-differentiation of resident astrocytes

et al. 2010

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“…There is the possibility that the increased extracellular levels of glutamate associated with loss of DA could result from downregulation of striatal GLT-1. Whereas some groups have reported downregulation of GLT-1 following dopaminergic lesioning (Holmer et al, 2005; Chung et al, 2008), others have observed an upregulation of striatal GLT-1 (Massie et al, 2010). We and others did not detect changes in striatal GLT-1 expression (Lievens et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Reverse microdialysis of a 5-HT2A receptor antagonist alters extracellular glutamate levels in the striatum of the MPTP mouse model of Parkinson’s disease

Ferguson

Nayyar

Ansah

2014

Neurochemistry International

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Clinical observations have suggested that antagonism of 5-HT2A receptors may benefit patients with parkinsonian symptomatology. The mechanism of the antiparkinsonian effects of 5-HT2A receptor antagonists has not been fully elucidated. We have shown that the selective 5-HT2A receptor antagonist M100907 [R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenethyl)]-4-piperidinemethanol] improved motor impairments in mice treated with the parkinsonian neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In Parkinson's disease (PD) patients and animal models of parkinsonism dopamine denervation is associated with increased cortico-striatal glutamatergic transmission. We hypothesized that 5-HT2A receptor antagonists may exert their antiparkinsonian effects by decreasing striatal glutamate. Here, using in vivo microdialysis, we have shown an increased basal level of extracellular striatal glutamate when measured three weeks after MPTP administration. The local administration of M100907 to the striatum significantly decreased striatal extracellular glutamate levels in MPTP-treated and saline treated mice. Basal extracellular serotonin (5-HT) levels were also elevated, whereas dopamine (DA) levels were significantly reduced in the striatum of MPTP-treated mice. Infusion of M100907 into the striatum produced no effect on dopamine or 5-HT levels. Local application of tetrodotoxin suppressed glutamate, 5-HT and DA concentrations in striatal dialysates in the presence or absence of M100907. The striatal expression of the glutamate transporter GLT1 was unchanged. However, there was an upregulation of the expression of 5-HT2A receptors in the striatum in MPTP-treated animals. Our data provide further evidence of enhanced glutamatergic neurotransmission in parkinsonism and demonstrate that blocking 5-HT2A receptors in the striatum will normalize glutamatergic neurotransmission.

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“…Recently, several studies demonstrated that EAAT2 expression is involved in PD. Decreased EAAT2 expression has been reported in animal models of PD, including the 6-hydroxydopaminelesioned PD model and the acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treated mouse model [145,146]. Recently, growing evidence shows ceftriaxone has beneficial effects in PD animal model, including the prevention of motor dysfunction, neuronal death, and PD related memory deficits [147][148][149][150][151][152].…”

Section: Parkinson's Diseasementioning

confidence: 99%

Glutamate transporter EAAT2: regulation, function, and potential as a therapeutic target for neurological and psychiatric disease

Takahashi

Foster

Lin

2015

Cell. Mol. Life Sci.

145

111

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Glutamate is the predominant excitatory neurotransmitter in the central nervous system. Excitatory amino acid transporter 2 (EAAT2) is primarily responsible for clearance of extracellular glutamate to prevent neuronal excitotoxicity and hyperexcitability. EAAT2 plays a critical role in regulation of synaptic activity and plasticity. In addition, EAAT2 has been implicated in the pathogenesis of many central nervous system disorders. In this review, we summarize current understanding of EAAT2, including structure, pharmacology, physiology, and functions, as well as disease relevancy, such as in stroke, Parkinson's disease, epilepsy, amyotrophic lateral sclerosis, Alzheimer's disease, major depressive disorder, and addiction. A large number of studies have demonstrated that up-regulation of EAAT2 protein provides significant beneficial effects in many disease models suggesting EAAT2 activation is a promising therapeutic approach. Several EAAT2 activators have been identified. Further understanding of EAAT2 regulatory mechanisms could improve development of drug-like compounds that spatiotemporally regulate EAAT2.

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Downregulation of glial glutamate transporters after dopamine denervation in the striatum of 6‐hydroxydopamine‐lesioned rats

Cited by 86 publications

References 79 publications

Effect of 6-hydroxydopamine (6-OHDA) on proliferation of glial cells in the rat cortex and striatum: evidence for de-differentiation of resident astrocytes

Effect of 6-hydroxydopamine (6-OHDA) on proliferation of glial cells in the rat cortex and striatum: evidence for de-differentiation of resident astrocytes

Reverse microdialysis of a 5-HT2A receptor antagonist alters extracellular glutamate levels in the striatum of the MPTP mouse model of Parkinson’s disease

Glutamate transporter EAAT2: regulation, function, and potential as a therapeutic target for neurological and psychiatric disease

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