Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Documenta Ophthalmologica
Published in: Documenta Ophthalmologica 3/2012

01-12-2012 | Original Research Article

The effects of excitatory amino acids and their transporters on function and structure of the distal retina in albino rabbits

Authors: E. Levinger, E. Zemel, I. Perlman

Published in: Documenta Ophthalmologica | Issue 3/2012

Login to get access

Abstract

Purpose

To study the physiological and pathological roles of excitatory amino acid transporters in the distal retina of albino rabbits.

Methods

Albino rabbits were injected intravitreally in one eye with different doses of l- or d-isomers of glutamate or aspartate, with mixtures of l-glutamate and antagonists to glutamate receptors or with inhibitors of glutamate transporters. The other eye was injected with saline, and served as a control. The electroretinogram (ERG) was recorded 4 h and 2 weeks after injection. At the end of the ERG follow-up period, retinas were prepared for light microscopy.

Results

The ERG b-wave was reduced and the a-wave augmented by both isomers of EAAs when tested 4 h after injection. Long-term (2-week) follow-up indicated severe damage to the retina by both isomers of EAAs. Antagonists to glutamate-gated ionic channels failed to protect the rabbit distal retina from permanent damage. Competitive inhibitors of GLAST-1 transporter were highly effective in blocking synaptic transmission in the OPL and in inducing permanent ERG deficit. Selective inhibition of the GLT-1 transporter caused short-term augmentation of the ERG and no permanent ERG deficit.

Conclusion

GLAST-1, the glutamate transporter of Müller cells, plays a major role in synaptic transmission within the OPL of the rabbit retina. Over-activation of GLAST-1 seems to induce permanent damage to the distal rabbit retina via yet unidentified mechanism.
Literature
1.
Cervetto L, MacNichol EF Jr (1972) Inactivation of horizontal cells in turtle retina by glutamate and aspartate. Science 178:767–768PubMedCrossRef
2.
Thoreson WB, Witkovsky P (1999) Glutamate receptors and circuits in the vertebrate retina. Prog Retin Eye Res 18:765–810PubMedCrossRef
3.
Wu SW (1994) Synaptic transmission in the outer retina. Ann Rev Physiol 56:141–168CrossRef
4.
Lucas DR, Newhouse JP (1957) The toxic effect of sodium l-glutamate on the inner layers of the retina. Arch Ophthalmol 58:193–201CrossRef
5.
Olney JW (1982) The toxic effects of glutamate and related compounds in the retina and the brain. Retina 2:341–359PubMedCrossRef
6.
Sisk DR, Kuwabara T (1985) Histologic changes in the inner retina of albino rats following intravitreal injection of monosodium l-glutamate. Graefe’s Arch Clin Exp Ophthalmol 223:250–258CrossRef
7.
Vorwerk CK, Lipton SA, Zurakowski D, Hyman BT, Sabel BA, Dreyer EB (1996) Chronic low-dose glutamate is toxic to retinal ganglion cells. Toxicity blocked by memantine. Invest Ophthalmol Vis Sci 37:1618–1624PubMed
8.
Rauen T, Rothstein JD, Wassle H (1996) Differential expression of three glutamate transporter subtypes in the rat retina. Cell Tissue Res 286:325–336PubMedCrossRef
9.
Lehre KP, Davanger S, Danbolt NC (1997) Localization of the glutamate transporter protein GLAST in rat retina. Brain Res 744:129–137PubMedCrossRef
10.
Harada T, Harada C, Watanabe M, Inoue Y, Sakagawa T, Nakayama N, Sasaki S, Okuyama S, Watase K, Wada K, Tanaka K (1998) Functions of the two glutamate transporters GLAST and GLT-1 in the retina. Proc Natl Acad Sci USA 95:4663–4666PubMedCrossRef
11.
Rauen T, Kanner BI (1994) Localization of the glutamate transporter GLT-1 in rat and macaque monkey retina. Neurosci Lett 169:137–140PubMedCrossRef
12.
Pow DV, Barnett NL, Penfold P (2000) Are neuronal transporters relevant in retinal glutamate homeostasis? Neurochem Int 37:191–198PubMedCrossRef
13.
Gaal L, Roska B, Picaud SA, Wu SM, Marc R, Werblin FS (1998) Postsynaptic response kinetics are controlled by a glutamate transporter at cone photoreceptors. J Neurophysiol 79:190–196PubMed
14.
Barnett NL, Pow DV (2000) Antisense knockdown of GLAST, a glial glutamate transporter, compromises retinal function. Invest Ophthalmol Vis Sci 41:585–591PubMed
15.
Matsui K, Hosoi N, Tachibana M (1999) Active role of glutamate uptake in the synaptic transmission from retinal nonspiking neurons. J Neurosci 19:6755–6766PubMed
16.
Higgs MH, Lukasiewicz PD (1999) Glutamate uptake limits synaptic excitation of retinal ganglion cell. J Neurosci 19:3691–3700PubMed
17.
Gibson BL, Reif-Lehrer L (1985) Mg+2 reduces N-methyl-d-aspartate neurotoxicity in embryonic chick neural retina in vitro. Neurosci Lett 57:13–18PubMedCrossRef
18.
Kashii S, Takahashi M, Mandai M, Shimizu H, Honad Y, Sasa M, Ujihara H, Tamura Y, Yokota T, Akaike A (1994) Protective action of dopamine against glutamate neurotoxicity in the retina. Invest Ophthalmol Vis Sci 35:685–695PubMed
19.
Abu El-Asrar AM, Morse PH, Maimone D, Torczynski E, Reder AT (1992) MK-801 protects retinal neurons from hypoxia and toxicity of glutamate and aspartate. Invest Ophthalmol Vis Sci 33:3463–3468
20.
Sucher NJ, Lipton SA, Dreyer EB (1997) Molecular basis of glutamate toxicity in retinal ganglion cells. Vision Res 37:3483–3493PubMedCrossRef
21.
Schuettauf F, Naskar R, Vorwerk CK, Zurakowski D, Dreyer EB (2000) Ganglion cells loss after optic nerve crush mediated through AMPA-kainate and NMDA receptors. Invest Ophthalmol Vis Sci 41:4313–4316PubMed
22.
Bresnick GH (1989) Excitotoxins: a possible new mechanism for the pathogenesis of ischemic retinal damage. Arch Ophthalmol 107:339–341PubMedCrossRef
23.
Mosinger JL, Olney JW (1989) Photothrombosis-induced ischemic neuronal degeneration in the rat retina. Exp Neurol 105:110–113PubMedCrossRef
24.
Louzada-Junior P, Dias JJ, Santos WF, Lachat JJ, Bradford HF, Coutinho-Netto J (1992) Glutamate release in experimental ischaemia of the retina: an approach using microdialysis. J Neurochem 59:358–363PubMedCrossRef
25.
Joo CK, Choi JS, Ko HW, Park KY, Sohn S, Chun MH, Oh YJ, Gwag BJ (1999) Necrosis and apoptosis after retinal ischemia: involvement of NMDA-mediated excitoxicity and P53. Invest Ophthalmol Vis Sci 40:713–720PubMed
26.
Dreyer EB, Grosskreutz CL (1997) Excitatory mechanisms in retinal ganglion cell death in primary open angle glaucoma (POAG). Clin Neurosci 4:270–273PubMed
27.
28.
Heidinger V, Hicks D, Sahel J, Dreyfus H (1999) Ability of retinal Müller cells to protect neurons against excitoxicity in vitro depends upon maturation and neuron-glial interactions. Glia 25:229–239PubMedCrossRef
29.
Kawasaki A, Otori Y, Barnstable CJ (2000) Müller cell protection of rat retinal ganglion cells from glutamate and nitric oxide neurotoxicity. Invest Ophthalmol Vis Sci 41:3444–3450PubMed
30.
Copenhagen DR, Jahr CE (1988) Release of endogenous excitatory amino acids from turtle photoreceptors. Nature 341:536–539CrossRef
31.
Greenberger LM, Besharse JC (1985) Stimulation of photoreceptor disc shedding and pigment epithelial phagocytosis by glutamate, aspartate and other amino acids. J Comp Neurol 239:361–372PubMedCrossRef
32.
Kleinschmidt J, Zucker CL, Yazulla S (1986) Neurotoxic action of kainic acid in the isolated toad and goldfish retina: I Description of effects. J Comp Neurol 254:184–195PubMedCrossRef
33.
Kleinschmidt J, Zucker CL, Yazulla S (1986) Neurotoxic action of kainic acid in the isolated toad and goldfish retina: II Mechanism of action. J Comp Neurol 254:196–208PubMedCrossRef
34.
Loewenstein A, Zemel E, Lazar M, Perlman I (1993) Drug-induced retinal toxicity in albino rabbits: effects of imipenem and aztreonam. Invest Ophthalmol Vis Sci 34:3466–3476PubMed
35.
Arriza JL, Fairman WA, Wadiche JI, Murdoch GH, Kavanaugh MP, Amara SG (1994) Functional comparisons of three glutamate transporter subtypes cloned from human motor cortex. J Neurosci 14:5559–5569PubMed
36.
Chatton J-Y, Shimamoto K, Magistretti PJ (2001) Effects of glial glutamate transporter inhibitors on intracellular Na+ in mouse astrocytes. Brain Res 893:46–52PubMedCrossRef
37.
Tano Y, Chandler DB, Machemer R (1980) Treatment of intraocular proliferation with intravitreal injection of triamcinolone acetonide. Am J Ophthalmol 90:810–816PubMed
38.
Zemel E, Loewenstein A, Lazar M, Perlman I (1993) The effects of myristyl γ-picolinium chloride on the rabbit retina: morphologic observations. Invest Ophthalmol Vis Sci 34:2360–2366PubMed
39.
Shahar J, Zemel E, Perlman I, Loewenstein A (2012) Physiological and toxicological effects of cefuroxime on the albino rabbit retina. Invest Ophthalmol Vis Sci 53:906–914PubMedCrossRef
40.
Hood DC, Birch DG (1992) A computational model of the amplitude and implicit time of the b-wave of the human ERG. Vis Neurosci 8:107–126PubMedCrossRef
41.
42.
Slaughter MM, Miller RF (1981) 2-amino-4-phosphonobutyric acid: a new pharmacological tool for retinal research. Science 211:182–185PubMedCrossRef
43.
Massey SC, Miller RF (1987) Excitatory amino acid receptors of rod- and cone-driven horizontal cells in the rabbit retina. J Neurophysiol 57:645–659PubMed
44.
Massey SC, Miller RF (1990) N-methyl-d-aspartate receptors of ganglion cells in rabbit retina. J Neurophysiol 63:16–30PubMed
45.
Bloomfield SA, Dowling JE (1985) Roles of aspartate and glutamate in synaptic transmission in rabbit retina. I. Outer plexiform layer. J Neurophysiol 53:699–713PubMed
46.
Normann RA, Perlman I, Daly SJ (1986) The effects of continuous superfusion of l-aspartate and l-glutamate on horizontal cells of the turtle retina. Vis Res 26:259–268PubMedCrossRef
47.
Gundersen V, Danbolt NC, Ottersen OP, Strom-Mathisen J (1994) Demonstration of glutamate/aspartate uptake activity in nerve endings by use of antibodies recognising exogenous d-asparate. Neurosci 57:97–111CrossRef
48.
Eliasof S, Arriza JL, Leighton BH, Kavanaugh MP, Amara SG (1998) Excitatory amino acid transporters of the salamander retina: identification, localization, and function. J Neurosci 18:698–712PubMed
49.
Schousboe A, Svenneby G, Hertz L (1977) Uptake and metabolism of glutamate in astrocytes cultured from dissociated mouse brain hemispheres. J Neurochem 29:999–1005PubMedCrossRef
50.
Karwoski CJ, Xu X (1999) Current source-density analysis of light-evoked field potentials in rabbit retina. Vis Neurosci 16:369–377PubMedCrossRef
51.
Lei B, Perlman I (1999) The contribution of voltage- and time-dependent potassium conductances to the electroretinogram in rabbits. Vis Neurosci 16:743–754PubMedCrossRef
52.
Lasater EM, Dowling JE (1982) Carp horizontal cells in culture respond selectively to l-glutamate and its agonists. Proc Natl Acad Sci USA 79:936–940PubMedCrossRef
53.
Nawy S, Jahr CE (1991) cGMP-gated conductance in retinal bipolar cells is suppressed by photoreceptor transmitter. Neuron 7:677–683PubMedCrossRef
54.
Morigiwa K, Vardi N (1999) Differential expression of ionotropic glutamate receptor subunits in the outer retina. J Comp Neurol 405:173–184PubMedCrossRef
55.
Reichenbach A, Kasper M, El-Hifnawi E, Eckstein A-K, Fuchs U (1995) Hepatic retinopathy: morphological features of retinal glial (Müller) cells accompanying hepatic failure. Acta Neuropathol 90:273–281PubMedCrossRef
56.
Reichenbach A, Stolzenburg J-U, Wolburg H, Hartig W, El-Hifnawi E, Martin H (1995) Effects of enhanced extracellular ammonia concentration on cultured mammalian retinal glial (Müller) cells. Glia 13:195–208PubMedCrossRef
57.
Bringmann A, Kuhrt H, Germer A, Biedermann B, Reichenbach A (1998) Mueller (glial) cell development in vivo and in retinal explant cultures: morphology and electrophysiology, and the effects of elevated ammonia. J Hirnfosch 39:193–206
58.
Pow DV, Robinson SR (1994) Glutamate in some retinal neurons is derived solely from glia. Neuroscience 60:355–366PubMedCrossRef
59.
Perlman I (2009) Testing retinal toxicity of drugs in animal models using electrophysiological and morphological techniques. Doc Ophthalmol 118:3–28PubMedCrossRef
Metadata
Title
The effects of excitatory amino acids and their transporters on function and structure of the distal retina in albino rabbits
Authors
E. Levinger
E. Zemel
I. Perlman
Publication date
01-12-2012
Publisher
Springer-Verlag
Published in
Documenta Ophthalmologica / Issue 3/2012
Print ISSN: 0012-4486
Electronic ISSN: 1573-2622
DOI
https://doi.org/10.1007/s10633-012-9354-x

Other articles of this Issue 3/2012

Documenta Ophthalmologica 3/2012 Go to the issue

Original Research Article

Assessment of macular function of glaucomatous eyes by multifocal electroretinograms

Original Research Article

Response properties of slow PIII in the Large vls mutant

Original Research Article

Motion and pattern cortical potentials in adults with high-functioning autism spectrum disorder

Original Research Article

Establishing baseline rod electroretinogram values in achromatopsia and cone dystrophy

Original Research Article

Cortical potentials after electrical intraneural stimulation of the optic nerve during orbital enucleation

Original Research Article

Detailed functional and structural characterization of a macular lesion in a rhesus macaque