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The Muller Cell:A Functional Element of the Retina

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The Muller Cell:A Functional Element of the Retina GLIA The Muller cell: a functional element of the retina Eric Newman and AndreasReichenbach Mullercellsare the principalglialcellsof the retin~ assumingmanyof the functionscarriedout by astrocytes,oligodendrocytesand ependymalcellsin other CNS regions.Miillercellsexpress numerousvoltage-gatedchannelsand neurotransmitterreceptors,whichrecognizea varietyof neuronalsignalsand triggercelldepolarizationand intracellularCa2+waves.In turn, Mullercells modulateneuronalactivitybyregulatingtheextracellularconcentrationofneuroactivesubstances, including:(1) K+,whichis transportedvia Mulle*cellspatial-bufferingcurrents;(2) glutamate andGABA, whicharetakenup by Mulle~cellhigh-affinitycarriers;and (3) H+,whichiscontrolled by the action of Mulleecell Na+-HCOJ- co-transport and carbonicanhydrase.The two-way communicationbetweenMullercellsandretinalneuronsindicatesthat Mullercellsplayan active role in retinalfunction. TrendsNeurosci. (1996) 19, 307-312 Muller-cellphysiology F THE TWO principal types of macroglial cells 0 in the brain, oligodendrocytes are completely Muller cells, like other glial cells, express a wide absentin the retinae of most speciesand astrocytesare variety of voltage-gatedion channels&lz.Their mem- present only in mammalian species,and then only in brane conductance is dominated by inward-rectifier the nerve fiber layer. In their stead, the Muller cell K+channels913,which give these cells an extremely serves as the principal glial cell of the retina. It per- low membrane resistance, ranging from 10 to 21 Mfl forms many of the functions subservedby astrocytes, in differentspecies14. The inwar&rectifier K+channels oligodendrocytes and ependymal cells in other are distributedin a highly non-uniform manner over regions of the CNS. the cell surface. In amphibian species, 80-90?40of all Just as the retina has proveda valuableand access- channels are localized to the endfoot at the retinal ible tissue for elucidating the cellular and network surface,whilein mammalianspecieswith vascularized propertiesof neurons, the Mullercell has servedas an retinae, channels are localizedto the surfaceendfoot, important model system for investigations of glial soma, and, in the cat, apical microvilli14.Muller cells cells. Duringthe past quarter century, the physiologi- of various species also possess delayed-rectifier,fast- cal and morphological propertiesof Mullercells have inactivating and Ca2+-activatedK+ channels, Na+ been studied extensively. (See Refs 1-3 for recent channels, and Ca2+channels8,11,12.These channels reviews.)The amphibian retina, with its large, easily probably do not modulate cell membrane potential dissociatedMuller cells, has been a particularlyuseful significantly, however, as their cellular conduc- preparationin studiesof cell function. tance are much smaller than that of the K+inward- Muller-cellmorphology rectifier channel. AmphibianMuller cells are coupled together by gap junctions, while mammalian cells Miiller cells are radial glial cells which span the are coupled to astrocytes lying at the surface of the entire depth of the neural retina&6(Fig. 1). They are retina*5. present in the retinae of all vertebrate species. Mullercells also expressmany types of neurotrans- EricNewmanis at Radiatingfrom the soma (in the inner nuclearlayer)is mitter receptors, including a GABA~receptor16,17and the Deptof an inwardly directed process that terminates in an severaltypes of glutamatereceptors18-20.They possess Physiology, expanded endfoot at the inner border of the retina, high-affinity uptake carriers for glutamate21-23and Universityof adjacent to the vitreous humor. Also projecting from GABA(Refs21,24). Minnesota, the soma is an outwardlydirectedprocessthat ends in Mtillercells of the salamanderexpressa number of Minneapolis, the photoreceptor layer. Microvilli project from this acid–basetransport systems,includingan electrogenic MN55455, USA, apical process into the subretinal space surrounding Na+–HC03-co-transporter,an anion exchanger and a and Andreas the photoreceptors. In mammalian species with Na+–H+exchangerz5,Z6.They also have high levels of Reichenbach is at vascularizedretinae, en passant endfeet contact and carbonic anhydrase,an enzyme that plays an impor- the PaulFlechsig surround blood vessels within the retina while the tant role in pH regulationby catalyzingthe hydration Institutefor Brain endfeet of some cells next to the vitreous humor of COZto H+and HC03- (Refs27,28). Research,Deptof terminate on surface blood vessels. Secondary How do these physiological properties contribute Neurophysiology, processes branching from the main trunk of Muller to glio-neuronal communication within the retina? LeipzigUniversity, cells form extensive sheaths that surround neuronal Doesneuronalactivity resultin changesin Muller-cell D-04109Leipzi& cell bodies, dendrites,and, in the optic-fiberlayer,the function? Can Muller cells modulate neuronal activ- Federa[Republicof axons of ganglion cells. ity? These questionswill be exploredin this review. Germany. Copyright 01996, Elsevier Science Ltd. All rights reserved. 0166- 2236/96/$15.00 PII: S0166-2236(96)10040-0 71M Vol. 19, No. 8, 1996 307 GLIA E. Newman and A. Reichenbach – Miiller cells Neurotransmitters Neurotransmittersreleasedfrom neurons constitute a second signaling mechanism by which neuronal activitycan modulateMullercells. Mullercells express a varietyof receptors,includingthose for amino acids, catecholamines, neuroactive peptides, hormones and growth factors16-Z0,J*S6.Generally, these receptors dis- play high binding affinities and pharmacological properties similar to those described in neurons. In most cases where electrophysiological studies have been performed,ligand binding elicits cell depolariz- ation, causedby direct opening of ion channels, as in the case of the GABA~receptor in the skate and baboon1617,or by second-messenger systems. For example, increases in glutamate, dopamine18’36and CAP thrombin10are all believed to depolarizeMuller cells by a secondmessenger-linkedreduction in K+conduc- tance in the cell. Carban dioxide Active retinal neurons (particularlyphotoreceptors in the dark) release C02, leading to substantial increases in extracellular Pco . Such increases can result in rapid intracellular a~idification in Muller cells. This acidification is generated largely by the action of the enzymecarbonic anhydrase28,and might modulate several pH-dependent functions of the Muller cell, including carrier-mediated glutamate uptake37, acid–base transport, and gap-junctional coupling. SignalingwithinMiiller cells Calcium Neurotransmittersand ions releasedby neurons can activate second-messenger systems within Muller cells. One prominent example is the elevation of [Ca2+]iwithin Muller cells, which can be triggeredby K+-induceddepolarizationas well as by activation of ligand-gatedreceptors1933.In dissociated salamander Muller cells, raising IK+]Oresults in an influx of Ca2+ (Ref. 33), presumably through voltage-gated Ca2+ channels, while in cultured rabbit cells, glutamate elicits a Ca2+influx through non-NMDAreceptors19.In Fig. 1. Drawing of Muller cell in the mammalian retina. Neuronal the absence of external Ca2+,stimulation of salaman- somata and processesare ensheathed by the processesof a Miller cell der Mullercells leadsto the releaseof Ca2+from inter- (shaded blue). Abbreviations: A, amacrine cel~ B, bipolar cell; C, cone nal storesandto increasesin [Ca2+]iwhich begin in the photoreceptor cel~’CAP, capillary; E~ Mii//er-ce// endfoot; G, ganglion apicalend of the cell and travelin a wave-likemanner cell; H, horizontal cel~ M, Mti//er cel~ MV, Mti//er-ce// microvilli; 1?,rod towardsthe cell endfoot33(Fig. 2). These intracellular photoreceptor cell. Modifiedfrom Ref.7. Ca2+waves can be stimulated by elevated K+,gluta- mate and ATP,as well as by caffeine and ryanodine.It is interesting to speculate that these Ca2+waves pro- Recognitionof neuronalsignalsby Mullercells vide a second pathway,independent of the neuronal Potassium network,for signalsto be relayedfrom the outerto the Many substances released from active neurons, inner retina. including K+,neurotransmittersand metabolizes(such In addition to the release of Ca2+from internal as COZ),can potentially modulate Muller-cellbehav- stores, several other second-messenger systems can ior. Important signalingfunctions have been ascribed be activated by signals derived from neurons. These to increases in the extracellular K+ concentration include the inositol phosphate and adenylate ([K+]O)Z’.Increasesin IK+]Oresult in rapidcell depolar- cyclase-cAMPsystems34r35. ization in Miillercells30and in sloweractivation of the Control of neuronalmicroenvironmentby MuHer (Na+,K+)-ATPase31.Localizedincreasesin IK+]Ogenerate cells K+spatial-bufferingcurrentswithin Mullercells, lead- ing to the redistribution of excess extracellular K+ Glial cells can modulate neuronal activity by con- and to the generation of field potentials within extra- trolling the concentration of neuroactive substances cellularspace32.Enhanced~+]0has alsobeen shownto in the extracellularfluid bathing CNS cells. The con- stimulate glycogenolysisin mammalian Miiller cells7, centrations of neurotransmittersand K+,for example, and can triggerincreasesin the intracellularCa2+con- are regulatedby glial-cell homeostatic mechanisms. centration ([Caz+]i)1933. Studies on Miiller cells have provided some of the 308 71NSVoL 19, ~0, 8,1996 E. Newman and A. Reichenbach – Mtiller cells GLIA clearest examplesof glial-cellcontrol of the neuronal microenvironment.
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