nucleusLowContralateralnucleus CorrespondingauthorNaoumPIssanissadrugsbsduchicagoedu TRENDSinNeurosciencesVol26No9September2003 ateachsoundfrequencyDuringdevelopmentthereforebothexcitato ID: 108302
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InhibitorycircuitsinsensorymapsdevelopthroughexcitationNaoumP.IssaDepartmentofNeurobiology,PharmacologyandPhysiology,TheUniversityofChicago,947E.58thStreetMC0926,Chicago,Illinois60637,USAInhibitoryandexcitatoryconnectionsareequalpartnersindeterminingneuronalresponseproperties.Althoughthedevelopmentandplasticityofexcitatorynetworkshavebeenheavilystudied,littleisknownabouthowinhibitorycircuitsdevelop.Inarecentstudy,GunsooKimandKarlKandlerhaveshownthat,asinthedevel-opmentofexcitatorycircuits,synapseeliminationandstrengtheningareimportantprocessesforthedevelop-mentofwell-organizedinhibitorycircuits.ThesensoryworldismappedwithgreatprecisionatmanylevelsoftheCNS.Theresponsepropertiesofthecellswithinthesemapsarederivedfromtheinteractionofexcitatoryandinhibitoryinputs.Althoughunderstandinghowtheexcitatoryinputsdeveloptheirpreciseconnec-tionshasbeenasigniÞcantfocusofdevelopmentalneurobiologyoverthepast40years,verylittleisknownabouthowinhibitorycircuitsdevelopinthecontextofasensorymap.Intheirrecentstudystudy,KimandKandlershowthatinhibitorycircuitsarereÞnedbysomeofthesameprocessesasexcitatorycircuits.ReÞnementofmapsinexcitatorynetworksReÞnementoftopographicalmapshasbeenobservedinmanyexcitatorynetworks.Inthevisualsystem,forexample,developmentalreÞnementisobservedatseverallevels.Projectionsfromtheretinatothelateralgeniculatenucleusareinitiallywidespreadandaresubsequentlytrimmeddowntoanarrowstripwithinthecorrecteyeeye.Similarly,projectionsfromthelateralgenicu-latenucleustotheprimaryvisualcortexareprunedfromaninitiallyexuberantarborizationintoeye-speciÞccor-ticalcolumnscolumns.Intheseexcitatorynetworks,muchofthereÞnementisduetoactivity-dependentplasticity.Inthevisualsystem,gradientsofephrinsandEphreceptorscontributetotheformationoftheinitialpatternofinnervationinnervationbutactivityintheretinaedrivesthereÞnementofeyemapsinthelateralgeniculatenucleusnucleusandofretinotopicmapsintheamphibianretinotectalsystemsystem.Inthecortex,unequalvisualactivityinthetwoeyescanreorganizeocular-dominancecolumnsduringadevelopmentalcriti-calperiodperiod.Basedonthedevelopmentoftheseandsimilarexcitatorynetworks,itseemsthatactivity-depen-dentplasticityisafundamentalmechanismfortheirAninhibitorycircuitintheauditorybrainstemWithinsensorysystems,mostinhibitoryconnectionsarelocal,arisingfrominterneuronsinterspersedamongexcitatoryneurons.Asaresult,ithasbeendifÞculttoisolateinhibitoryneuronsorpathwaystodeterminehowtheirspeciÞcconnectionsdevelop.KimandKandlertookadvantageoftheraresensorycircuitinwhichinhibitoryneuronsandtheiraxonaltargetsarewellseparated:themedialnucleusofthetrapezoidbody(MNTB)sendsglycinergicinputstothelateralsuperiorolive(LSO)which,intheneonatalrat,is0.5mmaway(Fig.11.Thisseparationislargeenoughtoallowstimulationatandrecordingfromwell-separatedlocations,butissmallenoughforbothnucleitobecontainedinasinglebrainTheinhibitoryprojectionsbetweentheMNTBandLSOarepartofanauditorycircuitthatcalculatesthepositionofasoundsourcebasedonthedifferenceinsoundintensitiesatthetwoears.AnLSOneuronreceivesexcitatoryinputsfromtheipsilateralsidedirectlyfromtheventralcochlearnucleus,andinhibitoryinputsfromthecontralateralsideroutedthroughtheipsilateralMNTB.Thus,asoundoriginatingontheleftsidewouldexcitetheleftLSO,butwouldinhibittherightLSO.TheLSOcontainsadetailedmapofsoundfrequencyFig.1),inwhichboththeexcitatoryandtheinhibitoryinputsarearrangedaccordingtotheircharacteristicfrequency.ThelocalizationofasoundsourceisperformedFig.1.Theinhibitorycircuitryofthesuperiorolivarycomplex.Aschematicofacoronalsectionthroughtheratauditorybrainstemisshown.Thelateralsuperiorolive(LSO)calculatesthelocationofasoundsourceintheipsilateralauditoryhemiÞeld.Itreceivesexcitatoryinputfromtheipsilateralcochlearnucleus,andinhibitoryinputfromthecontralateralsidethroughthemedialnucleusofthetra-pezoidbody(MNTB).Soundfrequencyismappedwithineachnucleus.Plusandminussymbolsindicateexcitatoryandinhibitoryconnections,respectively. nucleusLowContralateralnucleus Correspondingauthor:NaoumP.Issa(nissa@drugs.bsd.uchicago.edu). TRENDSinNeurosciencesVol.26No.9September2003 ateachsoundfrequency.Duringdevelopment,therefore,bothexcitatoryandinhibitoryinputsmustbecomerestrictedtothecorrecttonotopicpositionintheLSOLSO.BystudyingthepatternofprojectionsfromtheMNTBtotheLSOatdifferentdevelopmentalstages,KimandKandlerwereabletoshowthattheprojectionpatternisinitiallybroadandistrimmedbackovertime.ReÞnementofsensorymapsinaninhibitorynetworkHowever,thereisaproblemwiththeideaofreÞninginhibitorynetworksthroughactivity-dependentplasticity.MostsynapticlearningrulesfollowamodiÞedHebbÕsrulerule,suchthatconnectionsbetweenneuronsarestrength-enediftheÞringofthepresynapticandpostsynapticneuronsiscorrelatedandareweakenedifitisuncorre-[11,12].Incontrasttoanexcitatorysynapse,theÞringofaninhibitorypresynapticneuronisnecessarilyanti-correlatedwiththeÞringofitspostsynapticpartner.Basedonthestandardlearningrules,therefore,itwouldseemimpossibleforinhibitorycircuitstobereÞnedthroughthestrengtheningofsynapses.KimandKandlerÕsÞndingssuggest,however,thatthereÞnementoftheMNTBÐLSOinhibitorynetworkresultsfrombotheliminationandstrengtheningofsynapses.Usingaratbrainslice,KimandKandlerrecordedfromindividualLSOneuronsusingwhole-cellpatchclamp,whilestimulatingdifferentlocationswithintheMNTBthroughfocalphoto-uncagingofglutamateglutamate.TheregionoftheMNTBthatprojectstoasingletonotopiclocationintheLSOwasmappedoutbysystematicallyvaryingthelocationofglutamaterelease.BymappingthepatternofinhibitoryinputstotheratLSOatdifferentpostnatalages,itbecameclearthatthedevelopmentoftheseinhibitoryconnectionsfollowsthesamepatternasthedevelopmentofexcitatoryconnectionsFig.2).Initially[atpostnatalday(P)1],alargeregionoftheMNTBprojectstoagiventonotopiclocation.Bythetimehearingstarts(P11ÐP14),however,amuchsmallerregion(25%oftheoriginalsize)oftheMNTBprojectstoanygivenlocationwithintheLSO.DuringtheÞrsttwoweeksoflife,therefore,functionalsynapsesbetweentheMNTBandLSOareprunedawaytoleaveonlyconnectionsthatarisefromanarrowrangeofauditoryfrequencies.Atthesametimethatsynapsesarebeingpruned,theconnectionsthatremainbecomemoreeffective.TodemonstratetheincreasedeffectivenessofindividualÞbers,MNTBÞberswereelectricallystimulatedwithastimulusintensitylowenoughforpostsynapticresponsestobeobservedonly30%ofthetime.Atsuchlowprobabilitiesofapostsynapticresponse,eachpostsynapticresponsewasalmostcertainlyproducedbytheactivityofonlyasingleÞber.Usingthisprocedure,KimandKandlerfoundthatstimulationofasingleP14MNTBÞberproduced12timesasmuchpostsynapticcurrentasstimulationofaP1Þber.Althoughitisnotknownwhethertheincreaseincurrentisduetostrongerindividualsynapsesorthepresenceofmoresynapses,theincreasedeffectivenesssuggeststhatstrengtheningsynapticcon-nectionswithinarestrictedtargetisimportantinreÞningtheinhibitorynetwork.ExcitatoryGABAergicandglycinergicsynapsesRatherthanrelyingoninhibitoryinteractionstodrivethereÞnementofprojections,theMNTBÐLSOprojectionsappeartobereÞnedthroughexcitatoryglycinergicandGABAergicsynapses.ThetimecourseofreÞnementfollowsthedevelopmentofinhibitionintheMNTBÐLSOsystem.Asisseenduringthedevelopmentofotherinhibitoryneuronsneurons,theClreversalpotentialinneuronsoftheLSOisrelativelypositive(48mV)atbirthbutbecomesmorenegative(82mV)bythetimeofhearingonsetonset.DuringthereÞnementperiod,there-fore,glycinergicandGABAergicinputsdepolarizethepostsynapticcellcell,whichcanproduceincreasesinpostsynapticCaconcentrationandcanresultinactionaction.OnlytowardstheendofthereÞnementperioddotheglycinergicinputstotheLSOactuallyinhibititsactivity.ThecorrespondencebetweenthetimecourseofreÞne-mentandthedevelopmentofinhibitionsupportsamechanismforreÞnementthatreliesontheexcitatorypropertiesofimmatureglycinergicandGABAergicGABAergic.Accordingtothisproposedmechanism,spontaneousactivityintheMNTBÐLSOpathwaydrivespostsynapticactivityduringthereÞnementperiod.Simi-lartothemannerinwhichcurrentthroughNMDAchannelsmediatesLTPandLTD,correlatedpresynapticandpostsynapticactivitywouldproduceanincreaseinthepostsynapticCaconcentrationintheLSOneurons(asissuggestedbytheCaresponsesobservedinRefs[17,18]Atlocationswherethepostsynapticactivationisweak,asislikelyattheedgesofthebroadinnervationpatterninanimmatureLSO,synapseswouldbelost.Wherethepostsynapticactivationisstrong,asislikelyinthecenteroftheinnervationpatterninanimmaturemap,synapseswouldbestabilizedandadded.AttheendofthereÞnementperiod,afewdaysbeforetheonsetofhearing,thesynapsesbecomeinhibitory,andthismechanismforsynapticplasticityislostÐleavingawell-orderedinhibitorymapoftheipsilateralauditoryhemiÞeld.TheworkofKimandKandleraddssupporttothehypothesisthatplasticityatexcitatorysynapsessetsthecircuitryoftheinhibitorytonotopicmapintheLSO.Nonetheless,thisevidenceisonlycircumstantial.Fig.2.ThereÞnementofinputsfromthemedialnucleusofthetrapezoidbody(MNTB)tothelateralsuperiorolive(LSO).Justafterbirth[postnatalday(P)1],alargeregionoftheMNTBprojectstoanygivencellwithintheLSO.Thedistri-butionofMNTBneuronsthatprojecttoagivencellintheLSOshrinksoverthenexttwoweeks.ThecoloredregionsintheMNTBrepresenttherangeoffrequen-ciesthatprojectstothespeciÞclocationshownintheLSO. Ð LSOMNTBP14P1 TRENDSinNeurosciencesVol.26No.9September2003 Validationofthehypothesisawaitsdirectdemonstrationofactivity-dependentplasticityattheseimmaturesynapses,ofspontaneousactivityinthecircuit,andofdisruptionofnormalmapdevelopmentwhentheexcit-atoryGABAergicandglycinergicsynapsesareblocked.Justasthevisualsystemhasgivenusinsightintothedevelopmentofexcitatorymaps,theMNTBÐLSOsystemisbeginningtoprovideawealthofinformationonthedevelopmentofinhibitorymaps.AcknowledgementsWorkinmylaboratoryissupportedbytheBrainResearchFoundation.IthankAtulMallikandNaomiRuffforhelpfulcommentsonthemanuscript.1Kim,G.andKandler,K.(2003)Eliminationandstrengtheningofglycinergic/GABAergicconnectionsduringtonotopicmapformation.Nat.Neurosci.6,282Ð2902Shatz,C.J.(1983)TheprenataldevelopmentofthecatÕsretinogen-iculatepathway.J.Neurosci.3,482Ð4993Antonini,A.andStryker,M.P.(1993)Developmentofindividualgeniculocorticalarborsincatstriatecortexandeffectsofbinocularimpulseblockade.J.Neurosci.13,3549Ð35734Feldheim,D.A.etal.(1998)Topographicguidancelabelsinasensoryprojectiontotheforebrain.21,1303Ð13135Penn,A.A.etal.(1998)Competitioninretinogeniculatepatterningdrivenbyspontaneousactivity.279,2108Ð21126Cline,H.T.andConstantine-Paton,M.(1989)NMDAreceptorantagonistsdisrupttheretinotectaltopographicmap.413Ð4267Crowley,J.C.andKatz,L.C.(2002)OculardominancedevelopmentCurr.Opin.Neurobiol.12,104Ð1098Hubel,D.H.andWiesel,T.N.(1965)BinocularinteractioninstriatecortexofkittensrearedwithartiÞcialsquint.J.Neurophysiol.1041Ð10599Sanes,D.H.andFriauf,E.(2000)Developmentandinßuenceofinhibitioninthelateralsuperiorolivarynucleus.Hear.Res.147,46Ð5810Hebb,D.O.(1949)TheOrganizationofBehavior,Wiley11Lowel,S.andSinger,W.(1992)Selectionofintrinsichorizontalconnectionsinthevisualcortexbycorrelatedneuronalactivity.255,209Ð21212Hata,Y.andStryker,M.P.(1994)Controlofthalamocorticalafferentrearrangementbypostsynapticactivityindevelopingvisualcortex.265,1732Ð173513Callaway,E.M.andKatz,L.C.(1993)Photostimulationusingcagedglutamaterevealsfunctionalcircuitryinlivingbrainslices.Proc.Natl.Acad.Sci.U.S.A.90,7661Ð766514Owens,D.F.andKriegstein,A.R.(2002)IstheremoretoGABAthansynapticinhibition?Nat.Rev.Neurosci.3,715Ð72715Ehrlich,I.etal.(1999)Shiftfromdepolarizingtohyperpolarizingglycineactioninratauditoryneuronesisduetoage-dependentClJ.Physiol.520,121Ð13716Ben-Ari,Y.(2002)ExcitatoryactionsofGABAduringdevelopment:thenatureofthenurture.Nat.Rev.Neurosci.3,728Ð73917Kullmann,P.H.etal.(2002)GlycinergicandGABAergiccalciumresponsesinthedevelopinglateralsuperiorolive.Eur.J.Neurosci.1093Ð110418Kandler,K.etal.(2002)Excitatoryactionofanimmatureglycinergic/GABAergicsoundlocalizationpathway.Physiol.Behav.77,583Ð5870166-2236/$-seefrontmatter2003ElsevierLtd.Allrightsreserved.doi:10.1016/S0166-2236(03)00209-1 Making(a)senseofnon-visualocularphotoreceptionRussellN.VanGelderDepartmentofOphthalmologyandVisualSciences,DepartmentofMolecularBiologyandPharmacology,WashingtonUniversityMedicalSchool,CampusBox8096,660S.EuclidAvenue,StLouis,MO63110,USAAsubsetofintrinsicallyphotosensitiveretinalganglioncellstransduceinformationaboutambientlightingcon-ditionstoareasofthebraininvolvedintasksincludingentrainmentofthecircadianclock,pupillarylightreßexesandmelatoninsynthesis.Thephototransduc-tionsystem(s)utilizedbythesecellsareunknown.Mel-anopsinandcryptochromeshavebeenproposedascandidatephotopigmentsforthissystem.Recentanalysesofretinaldegeneratemicelackingmelanopsinorcryptochromesindicatesthatouterandinnerphoto-receptorscanbothcontributetonon-visualphoto-responses,andthatbothmelanopsinandcryptochromesplayimportantrolesinthisprocess.TheÞrstdeÞnitionforÔeyeÕintheOxfordEnglishDictionaryissimplyÔTheorganofsight(inmanandanimals)Õ.Butisthisthesolefunctionoftheeye?Overthepastdecade,asecondrolefortheeyehasbeenuncovered:evenintheabsenceofformvision,theeyecanserveasasensorforambientlighting,akintothelightmeterinacamera.Ahostoflight-regulatedfunctions,includingentrainmentofcircadianclocksclocks,suppressionofactivitybylightlight,photicsuppressionofpinealmelatoninmelatonin,andpupillarylightresponsesresponsesareretainedinmicethatareblindasaresultofmutationscausingcompleteornear-completedegenerationoftheclassicalphotoreceptors,therodsandcones.Theselight-responsivefunctionsarecontrolledbyaretinalphoto-receptorbecausemicelackingretinalganglioncellslosecircadianphotoresponses,behavioralmaskingandpupil-larylightresponsesresponses.Thediscoverylastyearofintrinsicallyphotoresponsiveretinalganglioncells(ipRGCs)hasgivennon-visualphototransductionananatomicalbasisbasis.BersonandcolleaguesusedretrogradedyetracingfromthecircadianpacemakingcellsintheratsuprachiasmaticnucleustodeÞnedirectretinohypothalamic-projectingganglioncells;onpatch-clamprecording,thesecellswerefoundtobe Correspondingauthor:RussellN.VanGelder(vangelder@vision.wustl.edu). TRENDSinNeurosciencesVol.26No.9September2003