Neuroscience201AReading

Module3–SynapticTransmission

Books/BookChapters:

FainG(2014)MolecularandCellularPhysiologyofNeurons,2ndedition,HarvardUniversityPress,Chapters8-10.WewillcoverthematerialinChapters9and10sparingly.

ShengM,SabatiniBL,SüdhofTC,eds.(2012)TheSynapse,ColdSpringHarbor,NY.(Excellentbook;perhapsworthaddingtoyourlibraryifyouendupfocusingonsynapsesforyourthesiswork.Thepreviousversion,2001,isalsogoodbutdated.)

JohnstonD,WuSM-S(1995)FoundationsofCellularNeurophysiology,MITPress,Cambridge,Massachusetts,Chapters11-13.

KandelER,SchwartzJH,JessellTM(2012)PrinciplesofNeuralScience,5thedition,McGrawHill,NewYork,NewYork,Chapters10,11,12,14.

NichollsJG,MartinAR,FuchsPA,BrownDA,DiamondME,WeisblatDA(2012)FromNeurontoBrain,5thedition,Sinauer,Sunderland,Massachusetts,Chapters9-12.

PurvesD,AugustineGJ,FitzpatrickD,HallWC,LaMantiaA-S,WhiteLE,eds.(2012)Neuroscience,5thedition,SinauerAssociates,Inc.,Sunderland,Massachusetts,Chapters5,6.

ReviewArticles:

EggermanE,BucurenciuJ,GoswamiSP,JonasP(2012)NanodomaincouplingbetweenCa2+channelsandsensorsofexocytosisatfastmammaliansynapses.NatRevNeurosci13:7-21.

FiorvanteD,RegehrW(2011)Short-termformsofpresynapticplasticity.CurrOpinNeurobiol21:269-274.

KavalaliE(2015)Themechanismsandfunctionsofspontaneoustransmitterrelease.NatureRevNeurosci16:5-16.

KochubeyO,LouX,SchneggenburgerR(2011)RegulationoftransmitterreleasebyCa2+andsynaptogagmin:insightsfromalargeCNSsynapse.TrendsNeurosci34:237-246.

NeherE,TaschenbergerH(2012)TransientsinglobalCa2+concentrationinducedbyelectricalactivityinagiantnerveterminal.JPhysiol591:189-195.

PangZP,SüdhofTC(2010)CellbiologyofCa2+-triggeredexocytosis.CurrTopCellBiol.22:596-505.

RudolphS,TsaiM-C,vonGersdorff,H,WadicheJ(2015)Theubiquitousnatureofmultivesicularrelease.TrendsNeurosci38:428-438.

SchneggenburgerR,RosenmundC(2015)MolecularmechanismsgoverningCa2+regulationofevokedandspontaneousrelease.NatureNeurosci18:935-941.

SüdhofTC(2012)Thepresynapticactivezone.Neuron75:11-25.

AssignedPaperforDiscussion:

KawaguchiS-Y,SakabaT(2015)Controlofinhibitorysynapticoutputsbylowexcitabilityofaxonterminalsrevealedbydirectrecording.Neuron85:1273-1288.

StudyQuestionsforDiscussion:

Thispaperpresentsadifferentstoryforthebasisofshorttermdepressionthanthatpresentedinlecture.Whatisthetake-homemessageofthispaper?

Thesynapsesstudied(largely)bytheauthorsareonesmadeinlong-termcultures.Onp.1273,theauthorsstate“Theseneuronsformsynapsessimilartothatobservedinintactpreparations.”Whatistheevidencethattheseconnectionsresemblethoseintheanimal?DoPCsappearsimilarincultureandintheanimal(seeFig.1)?

Onpage1273(secondcolumnnearbottom)theauthorssay“PCaxonsarerelativelythickandcanfaithfullytransmitsodiumAPsuptoover200Hz.”Whattotheymeanby“thick,”andwhatistheconnectionbetween“thick”andahighrateofAPtransmission.

Whatisthesmallmolecularweight“classical”transmitteratsynapsesbetweenPCsandneuronsinthedeepcerebellarnuclei?Permeabilitytowhichion(s)areenhancedbythistransmitter?Howdotheauthorsarrangeinthispreparationforthecurrentcarriedbythisiontobeinward?

Theauthorsvoltage-clampedPCsandusedtheclampcircuitrytoelicittrainsofAPsatvaryingfrequency(p.1274,secondcolumn).Doestheuseofvoltagestepsinthecellbodyinfluencetheshapeofthesignalintheterminal?Putanotherway,arethesignalsthatreachtheterminalreallyactionpotentials?

AttheendofthefirstsectionoftheResults,theauthors,inreferringtoFigure1,statethat“thedepressionmightbedue…to…alteredCa2+influx,conductionfailure,orattenuationofAPs.”Whycanweruleoutconductionfailure,basedontheresultsinFigure1?

TheCmmeasurementsproducesignalsthatgreatlyoutlasttheperiodofstimulation(Fig.2).Theauthorsstate(p.1275,column2)that“acontinuousincreaseinCmwasobservedlastingforapproximately1safterthedepolarizationceased,probablyreflectingasynchronousrelease.”Howlongdoyouthinkthatthesesignalslast?Isthereanyevidencefororagainstthesuggestionthatasynchronousreleaseexplainsthesignal?Doyouthinkthatthesesignalsarean“artifact?”

Thecalciumuncagingexperiments(Fig.2)suggesttotheauthorsthatthereisa~4thpowerrelationshipbetweenpeak[Ca2+]iandrelease.Whatistheevidenceforthis?

EarlyinthepapertheauthorssupportthenotionthatdepressioninPC-DCNsynapsesisnotdepletion-basedbyarguingthatpv(probabilityofreleaseofadocked/primedvesicle)issmall.Whatevidencedotheyhavethatpvissmall?

Figure3BcomparesanIPSCevokedbystimulatingtheterminalwithan“artificialactionpotential”andtheaveragespontaneouslyoccurringmIPSC.Isthishomologoustothe“direct”approachofmeasuringquantalcontent?WhatisthesourceofeventsthatgiverisetomIPSCs?Canyoumakeout“evenlyspacedpeaks”inFig.3C?

WhataretheinwardcurrenttransientsinFigure4A(right)?

WhatdoesFigure3Ishow?

Theauthorsuseantibodiesagainstvoltage-dependsodiumchannelstoconcludethatlabelingis“sparse”intheterminalscomparedtothenodesofRanvier(p.1281,firstcolumn).Doyouthinkthatthisevidenceaddsmateriallytothephysiologicalevidencepresentedearlier?

Oneofthebitsofevidencesuggestinginothersystemsthatdepletionofreleasablevesiclesisatleastpartlyresponsiblefordepressionisthatthereisaconsistentrelationshipbetweenpvanddepression:anythingthatincreasesE/IPSCsizebyalteringpvalsoincreasesdepression.Inoneinstancetheauthorslookattheeffectsofincreasing[Ca2+]ofrom2to4mM(SupplementalFig.6H).Whathappens?WhatdotheysayaboutthisexperimentinthelegendtofigureS6?WhatdotheysayaboutitintheResults(p.1283,firstcolumn)?WhydoestheTEAresult,citedonp.1283,suggestthatdepletionisnotplayingaroleinthissystem?

Thereisaveryinterestingdevelopmentonpp.1282-3,startingwiththepassage“BecauseculturedPCaxonterminalsfiredat~5Hzatrest…”(p.1282,secondcolumn,secondfullsentence).Howdotheyaccountforthisbasalfiringintheirsliceexperiments,whereevidentlythereisnobasalfiring?Whathappenswhentheyabandontheattempttoaccountforit(SupplFig6)?

What’syouroverallassessmentofthispaper?TheprincipalcontributionofthispaperisNOTthatitsupportsanon-depletionmodelfordepressionatthissynapse,sincethatwasacceptedmorethanadecadeago.Whatisthecontribution(s)ofthispaper?WhataspectsofthepaperpromptedtheeditorstopublishininNeuron?Whatwastheelapsedtimefrominitialsubmissiontoacceptance?