what neurochemistry tells us about the retina

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EDITORIAL What neurochemistry tells us about the retina Clin Exp Optom 2013; 96: 257–258 DOI:10.1111/cxo.12070 Erica L Fletcher MScOptom PhD Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, Victoria, Australia E-mail: e.fl[email protected] The salvaging of sight in those with vision- threatening retinal disease is one of the last frontiers of modern ophthalmology. Improvements in our understanding of the structure and function of the retina have been exponential over the last 50 years and instrumental in improving our understand- ing of the mechanisms of disease and treat- ment. The special article by Kalloniatis and colleagues 1 in this issue of Clinical and Experi- mental Optometry shows how understanding the neurochemistry of the retina has influ- enced our knowledge of the structure and function of the retina and how it changes in disease. An e-supplement to this paper is a massive database of amino acid profiles in the retina and will be a very important collation of data for researchers in this field. The e-supplement is open access, as is the Kalloniatis paper, and can be accessed either from the paper or from the home page of Clinical and Experimental Optometry at http:// onlinelibrary.wiley.com/journal/10.1111/ (ISSN)1444-0938 The amino acids glutamate, GABA and glycine are recognised as the main neuro- transmitters mediating communication be- tween the various neurons of the retina. Glutamate is known to mediate communica- tion between photoreceptors, bipolar cells and ganglion cells, 2 while GABA and glycine mediate communication between the lateral elements of the retina, amacrine and hori- zontal cells. By using sophisticated post- embedding immunocytochemical methods to label cells that contain glutamate, GABA and/or glycine, one can examine virtually every neuron in the retina. 3 As shown in this article by Kalloniatis and colleagues, 1 there are remarkable similarities in neurochemis- try across the animal kingdom. Indeed, the authors show that the neurochemistry of neurons in the primate retina is remarkably similar to those of crocodiles, cats, Port Jackson sharks and even kangaroos, despite these other animals having vastly different visual needs from our own. This neuro- chemical architecture is conserved through evolution, perhaps indicative of its impor- tance for vision. Aside from the observation that the retinae of our eyes are similar to a plethora of other animals, including a rather large pig found on the menu of some restaurants in South America (the peccary), the localisa- tion of amino acids also provides insights on how neurons change during disease. The e-supplement database (www.aminoacidim- munoreactivity.com) provides a wealth of information on how neurons change in retinal detachment, retinal dystrophy and following metabolic insult. A key finding generated from neurochemical analysis has been the wholesale changes that occur in inner retinal neurons well after the loss of photoreceptors in models of retinal dystro- phy. 4,5 Despite the inner retina looking rela- tively normal following photoreceptor loss when viewed using nuclear stains such as toluidine blue, immunolabelling with gluta- mate, GABA and glycine uncovers an array of changes in inner retinal neurons, includ- ing areas where neurons migrate in columns from the inner to outer retina, regions of the inner plexiform layer that are displaced to ectopic sites and aberrant connections between some neurons. 5 Glial cells also change, forming large scars that fragment the retina. This information has dramati- cally improved our understanding of retinal remodelling and plasticity in disease and may have implications for the optimal devel- opment of photoreceptor restorative thera- pies such as retinal implants. Localisation of amino acids provides more information than merely whether a neuro- nal type is present in the retina or not. The amino acid neurotransmitters glutamate and GABA are linked with metabolism by virtue of their dependence on the normal function of the retinal glia, Müller cells, for uptake, degradation and recycling. 6 Gluta- mate released from neurons is removed from the synaptic cleft by high affinity up- take into Müller cells and rapidly degraded to glutamine via the enzyme glutamine synthetase. Glutamine is then shuttled from Müller cells back into neurons, to act as a precursor for the formation of both gluta- mate and GABA. Similarly, GABA turnover is linked with metabolism because of high affinity uptake into glial cells and degrada- tion by one of the main metabolic cycles in cells, the Krebs cycle. The ‘GABA-shunt’ is recognised as a major contributor to the overall energy needs of the central nervous system. What this means is that evaluation of neurochemistry can provide informa- tion about the metabolic state of neurons. In situations where metabolism is affected, such as following ischaemia or retinal detachment, neurochemistry is altered. Evaluation of changes in neurochemistry in disease requires a statistically rigorous approach. Pattern recognition has emerged as one such tool that can very effectively quantify neurochemical changes in popula- tions of neurons across the retina. 7 Pattern recognition uses software originally devel- oped for analysing imagery from satellites, and traditionally has been used to ascribe unique identifiers or ‘signatures’ to crops, houses or other ground features in satellite photographs generated by imaging the earth through different filters. In an analo- gous fashion, retinal neurons that have been labelled by one or more of a series of amino acids can be identified by their unique amino acid signatures. Differences in the numbers of statistically different groups or classes across the retina can uncover altera- tions in the function of neurons, cell loss or changes in amino acid recycling. Examples of this are provided in the internet-based database. Finally, the nexus between neurochemis- try and neuronal function is important. Functional mapping using an organic cation called agmatine is useful for further CLINICAL AND EXPERIMENTAL OPTOMETRY © 2013 The Author Clinical and Experimental Optometry 96.3 May 2013 Clinical and Experimental Optometry © 2013 Optometrists Association Australia 257

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Page 1: What neurochemistry tells us about the retina

EDITORIAL

What neurochemistry tells us about the retina

Clin Exp Optom 2013; 96: 257–258 DOI:10.1111/cxo.12070

Erica L Fletcher MScOptom PhDDepartment of Anatomy and Neuroscience, TheUniversity of Melbourne, Parkville, Victoria, AustraliaE-mail: [email protected]

The salvaging of sight in those with vision-threatening retinal disease is one of thelast frontiers of modern ophthalmology.Improvements in our understanding of thestructure and function of the retina havebeen exponential over the last 50 years andinstrumental in improving our understand-ing of the mechanisms of disease and treat-ment. The special article by Kalloniatis andcolleagues1 in this issue of Clinical and Experi-mental Optometry shows how understandingthe neurochemistry of the retina has influ-enced our knowledge of the structure andfunction of the retina and how it changesin disease. An e-supplement to this paperis a massive database of amino acid profilesin the retina and will be a very importantcollation of data for researchers in this field.The e-supplement is open access, as is theKalloniatis paper, and can be accessed eitherfrom the paper or from the home page ofClinical and Experimental Optometry at http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1444-0938

The amino acids glutamate, GABA andglycine are recognised as the main neuro-transmitters mediating communication be-tween the various neurons of the retina.Glutamate is known to mediate communica-tion between photoreceptors, bipolar cellsand ganglion cells,2 while GABA and glycinemediate communication between the lateralelements of the retina, amacrine and hori-zontal cells. By using sophisticated post-embedding immunocytochemical methodsto label cells that contain glutamate, GABAand/or glycine, one can examine virtuallyevery neuron in the retina.3 As shown in thisarticle by Kalloniatis and colleagues,1 thereare remarkable similarities in neurochemis-try across the animal kingdom. Indeed, theauthors show that the neurochemistry ofneurons in the primate retina is remarkably

similar to those of crocodiles, cats, PortJackson sharks and even kangaroos, despitethese other animals having vastly differentvisual needs from our own. This neuro-chemical architecture is conserved throughevolution, perhaps indicative of its impor-tance for vision.

Aside from the observation that theretinae of our eyes are similar to a plethoraof other animals, including a rather large pigfound on the menu of some restaurants inSouth America (the peccary), the localisa-tion of amino acids also provides insightson how neurons change during disease. Thee-supplement database (www.aminoacidim-munoreactivity.com) provides a wealthof information on how neurons change inretinal detachment, retinal dystrophy andfollowing metabolic insult. A key findinggenerated from neurochemical analysis hasbeen the wholesale changes that occur ininner retinal neurons well after the loss ofphotoreceptors in models of retinal dystro-phy.4,5 Despite the inner retina looking rela-tively normal following photoreceptor losswhen viewed using nuclear stains such astoluidine blue, immunolabelling with gluta-mate, GABA and glycine uncovers an arrayof changes in inner retinal neurons, includ-ing areas where neurons migrate in columnsfrom the inner to outer retina, regions ofthe inner plexiform layer that are displacedto ectopic sites and aberrant connectionsbetween some neurons.5 Glial cells alsochange, forming large scars that fragmentthe retina. This information has dramati-cally improved our understanding of retinalremodelling and plasticity in disease andmay have implications for the optimal devel-opment of photoreceptor restorative thera-pies such as retinal implants.

Localisation of amino acids provides moreinformation than merely whether a neuro-nal type is present in the retina or not. Theamino acid neurotransmitters glutamateand GABA are linked with metabolism byvirtue of their dependence on the normalfunction of the retinal glia, Müller cells, for

uptake, degradation and recycling.6 Gluta-mate released from neurons is removedfrom the synaptic cleft by high affinity up-take into Müller cells and rapidly degradedto glutamine via the enzyme glutaminesynthetase. Glutamine is then shuttled fromMüller cells back into neurons, to act as aprecursor for the formation of both gluta-mate and GABA. Similarly, GABA turnover islinked with metabolism because of highaffinity uptake into glial cells and degrada-tion by one of the main metabolic cyclesin cells, the Krebs cycle. The ‘GABA-shunt’is recognised as a major contributor to theoverall energy needs of the central nervoussystem. What this means is that evaluationof neurochemistry can provide informa-tion about the metabolic state of neurons.In situations where metabolism is affected,such as following ischaemia or retinaldetachment, neurochemistry is altered.

Evaluation of changes in neurochemistryin disease requires a statistically rigorousapproach. Pattern recognition has emergedas one such tool that can very effectivelyquantify neurochemical changes in popula-tions of neurons across the retina.7 Patternrecognition uses software originally devel-oped for analysing imagery from satellites,and traditionally has been used to ascribeunique identifiers or ‘signatures’ to crops,houses or other ground features in satellitephotographs generated by imaging theearth through different filters. In an analo-gous fashion, retinal neurons that have beenlabelled by one or more of a series of aminoacids can be identified by their uniqueamino acid signatures. Differences in thenumbers of statistically different groups orclasses across the retina can uncover altera-tions in the function of neurons, cell loss orchanges in amino acid recycling. Examplesof this are provided in the internet-baseddatabase.

Finally, the nexus between neurochemis-try and neuronal function is important.Functional mapping using an organiccation called agmatine is useful for further

C L I N I C A L A N D E X P E R I M E N T A L

OPTOMETRY

© 2013 The Author Clinical and Experimental Optometry 96.3 May 2013

Clinical and Experimental Optometry © 2013 Optometrists Association Australia 257

Page 2: What neurochemistry tells us about the retina

segregating neurons into subclasses basedon their functional uptake of this com-pound.8 No agmatine is found in the mam-malian retina; however, when the retina isincubated in agmatine it is localised withinneurons, reflecting their activity. This isfurther accentuated, if the retina is incu-bated in agmatine together with a glutamatereceptor agonist. In this case, agmatine islocalised in those cells expressing that typeof glutamate receptor. Careful mapping ofbipolar cells in an animal model of retinaldegeneration using agmatine has revealedthat during the active phase of photore-ceptor death, ON bipolar cells, in particular,show aberrant glutamate receptor expres-sion (as determined by agmatine labelling)and function more like OFF bipolar cells.

The article by Kalloniatis and colleagues1

is a comprehensive resource for examiningthe neurochemical architecture of the verte-brate retina and how it changes in disease.Variations in amino acid neurochemistryhave been documented across the verte-brate world and in diseases, including retinaldetachment, retinal degenerations, retinalischaemia and retinal vascular diseases, suchas retinopathy in prematurity. The altera-tions in neurochemistry observed can reflectloss of specific cell classes, altered functionand/or changes in amino acid recycling.This information forms a foundation forunderstanding disease and how to bettertarget treatments.

REFERENCES1. Kalloniatis M, Loh CS, Acosta ML, Tomisich G, Zhu

Y, Nivison-Smith L, Fletcher EL et al. Retinal aminoacid neurochemistry in health and disease. Clin ExpOptom 2013: 96: 310–332.

2. Massey SC. Cell types using glutamate as a neuro-transmitter in the vertebrate retina. In: OsborneNN, Chader GJ. Eds. Progress in Retinal Research.Oxford: Pergamon Press, 1990. p 399–425.

3. Kalloniatis M, Fletcher EL. Immunocytochemicallocalization of the amino acid neurotransmitters inthe chicken retina. J Comp Neurol 1993; 336: 174–193.

4. Jones BW, Watt CB, Frederick JM, Baehr W, ChenCK, Levine EM, Milam AH et al. Retinal remodelingtriggered by photoreceptor degenerations. J CompNeurol 2003; 464: 1–16.

5. Marc RE, Jones BW, Watt CB, Strettoi E. Neuralremodeling in retinal degeneration. Prog Retin EyeRes 2003; 22: 607–655.

6. Bringmann A, Pannicke T, Grosche J, Francke M,Wiedermann P, Skatchkov SN, Osborne NN,Reichenbach A. Müller cells in the healthy and dis-eased retina. Prog Retin Eye Res 2006; 25: 397–424.

7. Marc RE, Murry RF, Basinger SF. Pattern recogni-tion of amino acid signatures in retinal neurons.J Neurosci 1995; 15: 5106–5129.

8. Marc RE, Kalloniatis M, Jones BW. Excitationmapping with the organic cation AGB2+. VisionRes 2005; 28: 3454–3468.

Editorial Fletcher

Clinical and Experimental Optometry 96.3 May 2013 © 2013 The Author

258 Clinical and Experimental Optometry © 2013 Optometrists Association Australia