what neurochemistry tells us about the retina
TRANSCRIPT
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
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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
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