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HARVARD NEUROBIO 204 - The Synaptic Mechanism

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The Synaptic Mechanism of Direction Selectivity in Distal Processes of Starburst Amacrine CellsIntroductionResultsReciprocal GABAergic Inhibition between Distal Processes of Neighboring SACsSAC Receptive Field Structure under Stationary Light StimulationSynaptic Inputs to SACs during Stimulus MovementSurround Feedback Inhibition during Centripetal Stimulus MotionLight-Evoked Ca2+ Responses in SAC Distal ProcessesDiscussionThe Basic Synaptic Mechanism Underlying Direction Selectivity in SACsCa2+-Dependent, Reciprocal GABAergic Inhibition at SAC Distal ProcessesSynaptic Inputs to SACs during CP and CF MotionsLight-Evoked Ca2+ Responses at SAC Distal ProcessesExperimental ProceduresRetinal Preparation and ElectrophysiologyLight Stimulation and Ca2+ ImagingAcknowledgmentsReferencesNeuron 51, 787–799, September 21, 2006 ª2006 Elsevier Inc. DOI 10.1016/j.neuron.2006.08.007The Synaptic Mechanism of Direction Selectivityin Distal Processes of Starburst Amacrine CellsSeunghoon Lee1and Z. Jimmy Zhou1,2,*1Department of Physiology and Biophysics2Department of OphthalmologyUniversity of Arkansas for Medical SciencesLittle Rock, Arkansas 72205SummaryPatch-clamp recordings revealed that distal pro-cesses of starburst amacrine cells (SACs) receivedlargely excitatory synaptic input from the receptivefield center and nearly purely inhibitory inputs fromthe surround during both stationary and moving lightstimulations. The direct surround inhibition was medi-ated mainly by reciprocal GABAAsynapses betweenopposing SACs, which provided leading and pro-longed inhibition during centripetal stimulus motion.Simultaneous Ca2+imaging and current-clamp record-ing during apparent-motion stimulation further dem-onstrated the contributions of both centrifugal ex-citation and GABAA/C-receptor-mediated centripetalinhibition to the direction-selective Ca2+responsesin SAC distal processes. Thus, by placing GABA re-lease sites in electrotonically semi-isolated distalprocesses and endowing these sites with reciprocalGABAAsynapses, SACs use a radial-symmetric cen-ter-surround receptive field structure to build a polar-asymmetric circuitry. This circuitry may integrate atleast three levels of interactions—center excitation,surround inhibition, and reciprocal inhibitions thatamplify the center-surround antagonism—to generaterobust direction selectivity in the distal processes.IntroductionThe detection of movement direction is an essentialvisual function. The first stage of direction selectivity(DS) is accomplished in the inner plexiform layer of theretina, where synaptic interactions enable On-off andOn direction-selective ganglion cells (DSGCs) to re-spond vigorously to a light stimulus moving in a particular(preferred) direction, but respond minimally to the samestimulus moving in the opposite (null) direction (Barlowand Hill, 1963; Barlow et al., 1964; Barlow and Levick,1965). While the retinal circuit subserving DS has beenused as a classic model system for studying neural com-putation in the CNS for over four decades (Taylor andVaney, 2003), the mechanism underlying DS remains elu-sive. Recent studies have made several important find-ings. First, the direction-selective response of On-offDSGCs originates mainly from presynaptic interactionsbecause the excitatory and inhibitory inputs to DSGCsare themselves directionally selective (Borg-Graham,2001; Fried et al., 2002, 2005; Taylor and Vaney, 2002).In particular, starburst amacrine cells (SACs) (Famiglietti,1983; Tauchi and Masland, 1984; Vaney, 1984) providespatially asymmetric inhibition to DSGCs (Fried et al.,2002). Ablation of SACs also abolishes DS and optoki-netic eye movement (Yoshida et al., 2001; Amthor et al.,2002). Second, because SACs have recently been shownto release GABA by a vesicular mechanism (Zheng et al.,2004), it is likely that the release sites are in the distal var-icose zone, where synaptic vesicles are concentrated(Famiglietti, 1991), suggesting that the distal varicosezone is the primary source of the asymmetric GABAinhibition of DSGCs. Third, the distal varicose processesof SACs themselves respond to centrifugal and cen-tripetal stimulus motion with direction-selective Ca2+signals (Euler et al., 2002). These findings lead to thecurrent theory that DS is mediated mainly by the direc-tion-selective GABA release from SACs, which actsasymmetrically on DSGCs from the null side (Taylorand Vaney, 2003, but see Fried et al., 2005; Oeschet al., 2005 for additional mechanisms). However, acentral question in this theory remains unresolved: howare direction-selective responses generated in distalSAC processes at the first place?Theoretically, direction-selective responses in SACprocesses may arise from two sources: intrinsic cellularproperties (Tukker et al., 2004) and network interactions(Borg-Graham and Grzywacz, 1992). While much of thecurrent attention focuses on the intrinsic properties ofSACs (Euler et al., 2002; Gavrikov et al., 2003; Ozaitaet al., 2004), the synaptic basis for direction-selective re-sponses in SACs remains unknown (Fried et al., 2005)and puzzling. On one hand, neighboring SACs overlapextensively, with a dendritic coverage factor (definedas the product of a SAC dendritic field area and theSAC density) as high as 30–70 (Tauchi and Masland,1984; Vaney, 1984; Famiglietti, 1985). The extraordinarilyhigh degree of cofasciculation and the presence offunctional GABAAreceptor-mediated synapses be-tween overlapping SACs (Zheng et al., 2004) suggestimportant synaptic interactions among SACs. On theother hand, because direct GABAergic input to SACshas not been characterized during stimulus motion (Tay-lor and Wassle, 1995; Peters and Masland, 1996), andbecause the spatial organization of the GABAergic inter-action between SACs is unknown (Zheng et al., 2004),there is as yet no evidence for an important role of anyGABAA-mediated synaptic interactions in the formationof DS in SACs (Euler et al., 2002).The goal of this study was to determine whether syn-aptic interactions have a role in the direction-selectiveresponses of SACs and, if they do, what the essentialsynaptic circuitry supporting these interactions is.Patch-clamp and Ca2+imaging experiments revealedthat the reciprocal GABAergic inhibition between SACsprovided a robust synaptic mechanism for DS in SACs.ResultsReciprocal GABAergic Inhibition between DistalProcesses of Neighboring SACsTo understand the spatial organization of synaptic inter-actions between SACs, dual


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