Role of retinal glial cells in neurotransmitter uptake and metabolism

Bringmann, Andreas; Pannicke, Thomas; Biedermann, Bernd; Francke, Mike; Iandiev, Ianors; Grosche, Jens; Wiedemann, Peter; Albrecht, Jan; Reichenbach, Andreas

doi:10.1016/j.neuint.2008.10.014

Cited by 220 publications

(204 citation statements)

References 285 publications

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“…2A). All astroglia robustly express the high-affinity glutamate/aspartate transporter (GLAST) (2). By crossing a BAC transgenic mouse expressing a tamoxifen-inducible form of Cre recombinase under the control of the GLAST promoter (GLAST-CreER T2 ) to the ROSA26stopYFP reporter line, we observed that YFP expression was selectively induced in Müller glia by postnatal day (P)26 after i.p.…”

Section: Resultsmentioning

confidence: 99%

“…The radial morphology of Müller glia creates a columnar matrix that maintains the laminar structure of the retina. Müller glia also perform a wide range of physiological tasks, including reuptake and metabolism of GABA and glutamate, water and ion homeostasis, and energetic support of photoreceptor cells (1,2). Müller glia also participate in regeneration of the 11-cis retinal chromophore used by cone opsins (3,4).…”

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confidence: 99%

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Injury-independent induction of reactive gliosis in retina by loss of function of the LIM homeodomain transcription factor Lhx2

Melo

Miki

Rattner

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Müller glia are the primary glial subtype in the retina and perform a wide range of physiological tasks in support of retinal function, but little is known about the transcriptional network that maintains these cells in their differentiated state. We report that selective deletion of the LIM homeodomain transcription factor Lhx2 from mature Müller glia leads to the induction of reactive retinal gliosis in the absence of injury. Furthermore, Lhx2 expression is also down-regulated in Prph2 Rd2/Rd2 animals immediately before the onset of reactive gliosis. Analysis of conditional Lhx2 knockouts showed that gliosis was hypertrophic but not proliferative. Aging of experimental animals demonstrated that constitutive reactive gliosis induced by deletion of Lhx2 reduced rates of ongoing apoptosis and compromised both rod and cone photoreceptor function. Additionally, these animals showed a dramatically reduced ability to induce expression of secreted neuroprotective factors and displayed enhanced rates of apoptosis in light-damage assays. We provide in vivo evidence that Lhx2 actively maintains mature Müller glia in a nonreactive state, with loss of function initiating a specific program of nonproliferative hypertrophic gliosis.development | neurodegeneration M üller glia are the primary glial cell type in the vertebrate retina (1). The radial morphology of Müller glia creates a columnar matrix that maintains the laminar structure of the retina. Müller glia also perform a wide range of physiological tasks, including reuptake and metabolism of GABA and glutamate, water and ion homeostasis, and energetic support of photoreceptor cells (1, 2). Müller glia also participate in regeneration of the 11-cis retinal chromophore used by cone opsins (3, 4). Although the genetic regulation of Müller glial development has been extensively studied (5-8), virtually nothing is known about the intrinsic transcriptional network that maintains these cells, or any other astroglial subtype, in their terminally differentiated state.Like other astroglia, Müller glia can be induced to undergo reactive gliosis in response to a broad range of physiological stresses and insults (9). Although the molecular signature of reactive gliosis can vary considerably among injury paradigms, reactive astroglia show a set of common features, including cellular hypertrophy, up-regulation of intermediate filament proteins, and, in most cases, down-regulation of glutamine synthetase (GS). Although induction of reactive gliosis is ubiquitous after diverse types of retinal injuries, its function remains ambiguous. The discovery that preconditioning by a wide range of stressors also induces reactive gliosis has led to the suggestion that, at least in its early stages, reactive gliosis represents an coordinated response aimed at mitigating damage to nearby neurons (9). Severe and prolonged reactive gliosis, however, is usually associated with reduced neuronal viability, and it is unclear what regulates this transition between protective and destructive gliosis. It is ...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Injury-independent induction of reactive gliosis in retina by loss of function of the LIM homeodomain transcription factor Lhx2

Melo

Miki

Rattner

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Thus, Müller cells may be a critical cell type in the initial pathogenesis of early retinopathy in type 2 diabetes with metabolic syndrome. They may be the origin of the modulation of multiple key functions in the course of retinopathy because they are involved, for example, in angiogenesis, 42 in the maintenance of the blood-retina barriers, 43 in neurotransmitter metabolism 44 and in retinal fluid homeostasis. 43 This finding suggests that Müller cell-related pathogenesis is a characteristic of type 2 diabetes with obesity and metabolic syndrome, because in STZ-induced diabetic rats, the reduction of b-waves typically occurs not before but concomitantly with changes in the amplitudes of oscillatory potentials.…”

Section: Discussionmentioning

confidence: 99%

Microangiopathy and visual deficits characterize the retinopathy of a spontaneously hypertensive rat model with type 2 diabetes and metabolic syndrome

et al. 2010

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Retinopathy has been increasing in prevalence as a consequence of type 2 diabetes and a cluster of coexisting risk factors characterized as the metabolic syndrome. However, the combined effects of these conditions on the retina are poorly understood. Therefore, we focused on the spontaneously hypertensive corpulent rat (SHR/N-cp), a model with type 2 diabetes, obesity and features of the metabolic syndrome to characterize retinal changes at a structural and functional level. SHR/N-cp males at 4 and 8 months of age were used in this study. Metabolic parameters and blood pressure were measured by standard methods. Morphology was investigated by histological techniques supplemented by nicotinamide adenine dinucleotide phosphate-diaphorase staining of whole mounts and fluorescein angiography to analyze the retinal vasculature. The in vivo function of the retina was examined by electroretinography (ERG). Obese SHR/N-cp rats were hypertensive and showed significant increases in body weight, serum levels of glucose, triglycerides, total cholesterol and urinary glucose excretion compared with lean controls (Po0.01 for each). Histology indicated an overall intact integrity of the retina and aspects of microangiopathy in obese SHR/N-cp rats. ERG revealed intact processing of light signals but significantly decreased amplitudes of b-waves for all (Po0.01) and of a-waves for some examined light intensities (Po0.05). Oscillatory potentials were significantly protracted (Po0.01), whereas amplitudes were not reduced. Microangiopathy and electroretinographic deficits combine to produce an early non-proliferative retinopathy phenotype in the obese SHR/N-cp rats. Thus, this model represents a valuable experimental tool to obtain further insights into the mechanisms of retinopathy in the context of obesity, type 2 diabetes and metabolic syndrome.

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“…52) In general, it is considered that Müller cells and retinal astrocytes, which are retinal glia, play a role in the elimination of L-Glu from the retinal ISF since EAAT1 is reported to be expressed in these glial cells. 53) Our study suggests the involvement of EAAT1 in L-Glu transport at the plasma membrane of retinal pericytes (Figs. 2-3, 6, Table 2), implying the participation of retinal pericytes in L-Glu elimination from the retinal ISF by EAAT1-mediated L-Glu uptake in a similar manner to Müller cells and astrocytes.…”

Section: Discussionmentioning

confidence: 51%

<i>In Vitro</i> Study of L-Glutamate and L-Glutamine Transport in Retinal Pericytes: Involvement of Excitatory Amino Acid Transporter 1 and Alanine–Serine–Cysteine Transporter 2

Akanuma

Zakoji

Kubo

et al. 2015

Biological & Pharmaceutical Bulletin

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L-Glutamate (L-Glu) is known to be a relaxant of pericytes and to induce changes in microcirculatory hemodynamics. Since the concentration of L-Glu which induces the dilation of retinal capillaries is reported to be high compared with the estimated concentration in the retinal interstitial fluid, it is hypothesized that some systems involving concentrative L-Glu release are present in retinal pericytes. The purpose of this study was to investigate the existence of L-Glu-storing systems, which contribute to autocrine L-Glu release, in retinal pericytes using conditionally immortalized rat retinal pericytes (TR-rPCT1 Key words excitatory amino acid transporter; L-glutamate; retinal pericyte; alanine-serine-cysteine transporter; L-glutamine Retinal pericytes reside within the basal lamina of retinal capillaries and communicate with the retinal capillary endothelial cells which form the blood-retinal barrier (BRB). 1,2)It is known that the contraction and relaxation of pericytes which are induced by physiological factors leads to a change in the diameter of the capillaries. [3][4][5] Because it has been reported that the diameter of capillaries in the central nervous system (CNS) affects the blood flow rate in the capillaries and, thus, the exchange of some compounds between the circulating blood and retina, 6) it is very important to identify the regulatory mechanisms governing the contraction and relaxation of retinal pericytes.L-Glutamate (L-Glu) is known as a relaxant of pericytes and Peppiatt et al. have reported that L-Glu treatment induces dilation of the retinal capillaries. 7) Regarding the mechanism for the L-Glu-induced dilation of retinal capillaries, it has been proposed that L-Glu induces the production of nitric oxide (NO), a relaxant of the cells, and inhibits Ca 2+ influx in retinal pericytes, thereby relaxing the pericytes. 7,8) An in vitro analysis has indicated that this L-Glu-induced NO production occurs in the presence of L-Glu at a concentration of more than 1 mM. 8) In addition, the dilation of retinal capillaries accompanied with pericytes was induced by treatment with 500 µM L-Glu.7) The compounds between the retinal interstitial fluid (ISF) and vitreous humor are considered to be freely exchangeable, and the concentration of L-Glu in the vitreous humor has been reported to be 444 µM in rats.9) Because the L-Glu level in the retinal ISF seems to be low compared with the concentration which induces dilation of the retinal capillaries and relaxation in the pericytes, it is possible that some mechanisms for concentrative L-Glu release are present in retinal pericytes and/or the cells surrounded by the pericytes. In neuronal cells, the packing of L-Glu into synaptic vesicles up to concentrations as high as 100 mM and exocytotic release of L-Glu in the vesicles into the synaptic cleft have been reported. [10][11][12] It has also been reported that the uptake of L-Glu from the cytoplasm of neurons into synaptic vesicles involves the vesicular L-Glu transporters (VGLUTs) which belong to the so...

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Role of retinal glial cells in neurotransmitter uptake and metabolism

Cited by 220 publications

References 285 publications

Injury-independent induction of reactive gliosis in retina by loss of function of the LIM homeodomain transcription factor Lhx2

Injury-independent induction of reactive gliosis in retina by loss of function of the LIM homeodomain transcription factor Lhx2

Microangiopathy and visual deficits characterize the retinopathy of a spontaneously hypertensive rat model with type 2 diabetes and metabolic syndrome

<i>In Vitro</i> Study of L-Glutamate and L-Glutamine Transport in Retinal Pericytes: Involvement of Excitatory Amino Acid Transporter 1 and Alanine–Serine–Cysteine Transporter 2

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