神元發(fā)生與突觸形成

神經(jīng)元發(fā)生與神經(jīng)元發(fā)生與突觸形(Neuronalgenesisandsynaptic崔彩北京大學(xué)神經(jīng)科學(xué)研究所/基礎(chǔ)醫(yī)學(xué)神經(jīng)生物學(xué)NeuroscienceResearchInstitute,PekingEmail:clcui@;1About100billionAbout100billionneuronsinthebrain–preciselyinterconnectamongthem–tocodetheintricateinformationandtoregulatethebehavioralresponse,suchassense,movementandcognition,……Asa2ComponentsofthematuremammalianretinogeniculocorticalNeurogenesisduringembryoThegenesisofThesynapticNeurogenesisinSubventricularNeurogenesisduringembryoThegenesisofThesynapticNeurogenesisinSubventricularzone(SVZ)andsubgranularzoneNeurogenesisisdifferenceintheCNSandtheTheplasticityof–Eliminationofcellsorsynapses(PCD/Activity-dependentsynapticElementarymechanismsofcorticalsynapticConceptandimportanceofthecriticalConcluding3NeurogenesisduringembryoFromtheneuralNeurogenesisduringembryoFromtheneuraltubetotheprimordialTheentirenervoussystemarisesfromtheTheinductionandpatternduringtheNS誘導(dǎo)(induction)：胚胎發(fā)育過程或傳遞誘導(dǎo)分子的細(xì)胞是誘導(dǎo)或結(jié)構(gòu)稱反應(yīng)者(reactor)。Neuronalprogenitor對內(nèi)外環(huán)境改4FormationoftheneuraltubeandneuralDorsalFormationoftheneuraltubeandneuralDorsalCrossNeuraltubeNeuralcresttheCNS腦、脊髓thePNS(12腦神經(jīng)、31對脊神經(jīng)、神經(jīng)節(jié)5Somites theskeletalandmuscleneuralFormationoftheneural-TheprimitiveembryonicCNSbeginsasneuralFormationoftheneural-TheprimitiveembryonicCNSbeginsasathinsheetofectoderm(neuralplate)inducedbysignalsfromadjacentmesoderm,theneuralplateispatternedalongitsdorsoventralaxisformation.ThefirststepindevelopmentoftheNSistheformationofneuralgroove,itswallwascalledneuralfolds,thatcometogetherandfuse,formingtheneuralAfterthen,theventraltissueintheneuralneural-neural-tubenotochord,thedorsaltissuetheneuraltubeepidermalneural67cranialneuropore,somite,caudalneuropore,Thethreeprimarybrain anlageoftheTelencephalon:2Thethreeprimarybrain anlageoftheTelencephalon:2cerebralWhitecortex;Olfactorybulb;Internalcapsule;…Dorsalthalamus;Thirdventricle;…Retina;OpticOpticRostral–Cerebellum,Caudal–8Function:sensorysystem; Spinal99Thegenesisof-Thegenesisof-Thefirststepinwiringthenervoussystemtogetheristhegenerationofneurons.-NeuronalstructuredevelopsinthreemajorCellCellCellCell-InductionduringtheCell-InductionduringtheneuronalNeuralInductiveCellMarginalMarginalCellMarginalMarginalWalloftheCellACellAcellintheventricularzoneextendsaprocessthatreachesupwardtowardthepia.Thenucleusofthecellmigratesupwardfromtheventricularsurfacetowardthepialsurface,thecell’sDNAiscopied.Thenucleus,containingtwocompletecopiesofthegeneticinstructions,settlebacktotheventricularThecellretractsitsarmfromthepialsurface.Thecelldividesintwo.cellcell-acharacteristicofthechoreographyofcell1.cellproliferation1.cellproliferation-FateofthenewlyformeddaughterBothdaughtercellscleavedverticallyfromtheprecursorremainintheventricularzonetodivideagainandagain.ThismodeofcelldivisionpredominatesearlyindevelopmentfiexpandthepopulationofneuronalprecursorThebothcellscleavedhorizontallyfromtheprecursor,onemigratesawaytotakeupitspositioninthecortex,whereitwillneverdivideagain.Theotherdaughterremainsintheventricularzonetoundergomoredivision.Thismodepredominateslaterindevelopmentneuronal1.cellHowdoesthecleavage1.cellHowdoesthecleavageplaneduringthecelldivisiondeterminethecell’s-ThedistributionofcellconstituentsintheprecursorIthasbeen?Thegeneexpressionoftheprecursorisregulatedbyitstranscriptionfactors.Exp:Notch-1,“unopposed”bynumb,activatesthegeneexpressionthatthecelltoceasedivisionandmigrateawayfromtheventricularzone.?Ventricularzoneprecursorcellsrepeatedthispatternuntilalloftheneuronsofthecortexhavebeengenerated.Thecleavagehavebeenbasicallyfinishedonpregnantfifthmonthinhuman.Inhuman,mostneocorticalneuronsarebornbetweenthefifthweekandfifthmonth?gestation(pregnancy),andpeakingattheastonishingrateof250,000newneurons16CellCellThedaughtercellsfromtheprecursorsthatimmatureneuronarecalledTheradialglialcellsprovideascaffoldforthemigrationoftheThefirstmigrationneuroblastsawayfromtheventriculartoformcortical-Thisfigureshowsneuroblastscrawlingalongthethinprocessesoftheradialgliatothecorticalplate,whichformsjustunderthemarginalzone2.Inside-out2.Inside-outdevelopmentoftheThefirstcellsmigratedtothecorticalplate-formtheAsthesecellsdifferentiateintoneurons–becomelayerVIcells-migratepastandcollectinthecorticalplate.Thisprocessrepeatsagainandagainuntilalllayersofthecortex–thesublateneuronsdisappear3.Cell-Theprocessinwhicha3.Cell-Theprocessinwhichacelltakeontheappearanceandcharacteristicsofaneuronisknownascelldifferentiation.Differentiationistheconsequenceofaspecificspatiotemporalpatternofgeneexpression.Differentiationoftheneuroblastintoaneuronbeginswiththeappearanceofneuritessproutingoffthebody(allsame–axonanddendriteatfirst).Thedifferentiationisprogrammedwellbeforetheneuroblastarrivesatitsfinalrestingplace.Thecomplexityofdendritictreeisnotentirelypreprogrammed.Thefinestructure--axonsanddendritesalsodependson“environmental”factorsintheSynapseReview：definition,classify,SynapseReview：definition,classify,Model(chemicalsynapseEM:chemicalEM:chemicalEM:Genesisofconnection:Genesisofconnection:forThethreephasesofPathwayselection–pathAddressselection–ThethreephasesdependsDirectcell-to-cellContractbetweencellsandextracellularsecretionsfromotherCommunicationviaactionpotentialsandsynaptic1.ThegrowingThe1.ThegrowingThegrowingtipofaneuriteiscalledagrowthcone,whichisspecializedtoidentifyanappropriatepathforneuriteelongation.StructureandfeaturegrowthGrowthconein-takesholdofthesubstrateandpulltheadvancingGCforward-probetheenvironment,movinginandoutoftheCelladhesionmoleculesCelladhesionmolecules2.AxonguidanceandguidanceFunctionchangesofmicrobubulesand2.AxonguidanceandguidanceFunctionchangesofmicrobubulesandactin—withingrowthconeSpecificControllinggrowthconeinGuidancechemoattractionandactinsconcentrateinforepartofachemorepulsionandactinsdisappearinforepartofaChemoattractionandNetrinspurstheChemoattractionandNetrinspurstheaxongrowthtowardtheSlittheaxontheThereceptorsofNetrinandSlitareberegulatedinvaryingfromonesideofthemidlinetootherChemoaffinityEstablishingretinotopyinChemoaffinityEstablishingretinotopyinthefrogrestinotecalRogerSperryhadExperimentinembryofrog,retinacellstillcouldformthesynapseonitstargetpreciselyiftheeyeballisberotated180,onlyoptic-movementreflexdirectionmistake.3.SynapseWhen3.SynapseWhenthegrowthconecomesincontactwithitstarget,asynapsewillbeThedetailsofmechanismsofsynapseformationintheCNSarestillMostofthedatacomesfromstudiesoftheneuromuscularExp.StepsintheformationofaTheGMNterminalsecretesfiagrin,(Ca+entryintotheGCtriggersneuro-transmitterreleaseandchangesinthecytoskeletonfi adheretoitspost-synapsepartner)AgrininteractswithMuSKinthemuscularcellmembrane.TheclusteringofAchreceptorsthepostsynapticmembraneviatheactionofrapsyn(likeashepherdgatherthereceptorsatthe?Neurogenesis(birthofneurons):the?Neurogenesis(birthofneurons):theprocessbywhichneuronsaregeneratedfromneuralstemcellsandneuralprogenitorcells.?Adultneurogenesis:adultmammalianbrainisstillcapableofmitosisandthenewlygeneratedcellsdifferentiateintoneuronsthatmigratetointegratecircuitries.(AltmanJ,Science,–Subventricularzone–SubgranularzoneNeurogenesisintheadultNeurogenesisintheadultStudyin1980s?Althoughmostofthedivisionactionoftheprecursorsisoverwellbeforebirth,theadultSGZandSVZretainssomecapacitytogeneratenewon…NeurogenesisintheadultbrainisfartoolimitedtorepairCNSdamage.??AmigratingAmigratingcellrecordedintissue3.Differentiationof3.Differentiationofcortical-AsomatotopicmapofthefacialvibrissaeonmousecerebralpositionofthemajorvibrissaeonthevibrissaeregionofBarrelsinNiss-Whydon’taxonWhydon’taxonregenerateinourFigThecriticaldifferenceseemstobethedifferentenvironmentsoftheCNSandPNS.Intheearly1980s,AlbertAguayaetal.atMontrealGeneralHospitaltestedthisideainveryimportantexperimentshowedasFigA.MartinSchwabetal.inZurichuniversitydemonstratedthatCNSneuronsgrownintissuecultureextendaxonsalongsubstratespreparedfromSchwanncellsbutnotfromoligodendroglia.ThisfindingledtothesearchforglialfactorsthatinhibitaxongrowthintheCNS,andamoleculecallednogowasfinallyidentifiedearlyin2000.Anti-nogo(antibody)calleIN-1hasbeenraised,theminjectedtheantibodyintoadultratsafterspinalcordinjury.Thistreatmentenabledabout5%oftheseveredaxonstoregenerate…VoluntaryrunningVoluntaryrunningincreasesneurogenesisandpromotesforgettinginadultmiceKatherineG,etal,2014May,IncreasingNeurogenesisIncreasingNeurogenesisPromotesForgettinginAdultNeuronalmorphologicalresponsesto②Neuronalmorphologicalresponsesto②①③RepeatedScience.2010Jan8;327(5962):213-6;BiolPsychiatry.2010Aug1;68(3):249-PrenatalalcoholexposurePrenatalalcoholexposureinduceslong-termchangesindendriticspinesandsynapsesinousevisualcortexAlcoholAlcohol.2010Jul-Aug;45(4):312-TheplasticityofTheeliminationTheplasticityofTheeliminationofcellsorsynapses(PCD/ElementarymechanismsofcorticalsynapticConceptandimportanceofthecriticalTheeliminationofcellsandTheeliminationofcellsand-Cell?Entirepopulationsofneuronsareeliminatedduringpathwayformation,aprocessknownasProgrammedcelldeath(PCDorapoptosis).?Matchinginputswithtargetsbytheselectivecelldeath.?Theinputneuronswillcompetewithoneanotherforlimitedquantitiesoftrophicfactorsproducedbythetargetneurons.-Changesinsynaptic-Changesinsynaptic?Eachneuroncanreceiveonitsdendritesandsomaafinitenumberofsynapsescalledsynapticcapacity.Peaksearlyindevelopmentandthendeclines.Especiallyinadolescentofmacaquemonkeyinvisualcorticaldeclinedbymostly50%,(5000persecond).Ausefulmodelsystemforthestudyofsynapticelimination:effectofpostsynapticAChR,basalmembraneofmuscularfibrilonneuromuscularsynaptic??2.Activity-dependent2.Activity-dependentsynapticSynapticsegregation分離Synapticsegregation分離Thetwoinputneuronsinoneeye(top)fireatthesametimethisissufficienttocausethetopLGNtargetneurontofirebutnotthebottomThisisthesamesituationasinparta,exceptthatnowthetwoinputneuronsintheothereye(bottom)areactivesimultaneously,causingthebottomtargetneurontofire.Overtime,neuronsthatfiretogetherwiretogether.Noticealsothatinputcellsthatfireoutofsyncwiththetargetlosetheirlink.SegregationofoculardominanceSegregationofoculardominancecolumnsincatstriateInitiallytheinputsfromtheLGNservingtheeyes(differentcolour)areintermingledinlayerIV.OverthecourseoffetalandearlytheinputsfromtheeyessegregateintooculardominancecolumnsinlayerIV.-Modificationof-ModificationofoculardominancestripesaftermonocularTorstenAnormalAmonkeythathadbeenmonocularlydeprivedfor22months,startingat2weeksofage.Thenondeprivedeyehasbeeninjected,revealingexpandedoculardominancecolumnsinlyerIV.-electrophysiologicalrecordingfromtheneuroninstriate-Excitatorysynaptic-ExcitatorysynaptictransmissionintheimmaturevisualNMDAreceptorssignalcoincidentpre-andpostsynapticactivity–synapsesexcitatorysynapseNMDAreceptorsactivatedbysimultaneouspresynapticandpostsynaptica:Presynapticactivationcausesthereleaseofglutamate,whichactsonpostsynapticAMPAreceptorsandNMDAreceptors.Atthenegativerestingmembranepotential,theNMDAreceptorspasslittleioniccurrentbecausetheyareblockedwithMg2+ions.b:IfglutamatereleasecoincideswithdepolarizationsufficienttodisplacetheMg2+ions,thenCa2+willenterthepostsynapticneuronviatheNMDAr6ceptor.LTPandsynapticLTPandsynapticformationduringa:Aelectricstimulation(onpresynapticaxon)evokesanactionpotential(EPSPs)fromthepostsynapticneuron.b:LTPistheresultingenhancementofsynaptictransmission,whichischangedbystrongNMDAreceptorc:LTPatmanysynapsesisassociatedwiththeinsertionofAMPAreceptorsintosynapsesthatpreviouslyhadnone.Alonger-termconsequenceisthesplittingofpotentiatedsynapsestoformnewsitesofNMDAactivition→C