BIPN 144 Week 9 Notes(part 1)

BIPN 144 Week 9 Notes(part 1) - BIPN144Week9Notes(Part1...

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Unformatted text preview: BIPN144Week9Notes(Part1) Note:ThishasnotbeenreviewedbyDr.Bierandmayhaveerrors.Always trusttheprofessoroverthesenotes. DrBierStartedoffthedaybygoingoversomebasicsofneurophysiology.Ingeneral, inputsapproachtheneuronthroughthedendrites.Actionpotentialspropagate fromthecellbody,downtheaxontowardtheterminals. Therestingpotentialofaneuronisabout60mV,whichmeansthattheinsideofthe neuronismorenegativethanthesurroundingenvironment(negativeinside, positiveoutside).Additionally,theconcentrationsofNa+andCA++arehigher outsideofthecell,whileK+concentrationishigherinsidethecell. Asaneurondepolarizes,itbecomesmorepositive(usuallybecauseofNa+andCa++ ionsflowingintotheneuron).Ifitdepolarizestoasetpointcalledthethreshold,an actionpotentialwillfire.Atthreshold,awholebunchofvoltagegateNa+channels openup,allowingNa+torushintotheneuron,makingitpositive.Whenthingsget reallypositive,someK+channelsopenup,allowingK+torushoutofthecell, bringingthemembranepotentialbackdowntoabout60mV.Thresholdisusually between60and0mV.Whentheactionpotentialreachestheterminal,Ca++rushes intotheterminalresultinginthereleaseofneurotransmitters,fromvesicles,into thesynapse.Abunchoflittleenzymesandreuptakepathwaysexisttocutup and/orreabsorbtheneurotransmitters. Itusuallytakesmorethanoneactionpotentialtoinitiateanactionpotentialinthe postsynapticneuron.AsubthresholdexcitatorysignaliscalledanEPSP(itcausesa milddepolarization),ansubthresholdinhibitorysignaliscalledanIPSP(itcausesa mildhyperpolarization. Inadevelopingneuron,vesiclesareproducedjustpriortotheaxonmakingcontact withitstarget.Near/atthetarget,collapsinscollapsethegrowthcone,andhelp initiatetheprocessofgeneratingasynapse. Wethenfocusedinontheneuromuscularjunction(NMJ).Undernaturalconditions, oneneuroninnervatesonemusclefiber.Unlikeneurontoneuronconnections,ifa motorneuronfiresontoitsmusclefiber,themusclewilldepolarizeandcontract. Onepresynapticactionpotential=onemuscledepolarizationevent.Themain neurotransmitterinvolvedinthisprocessinAcetylcholine(Ach).Acetylcholine EsteraseisanenzymethathangsoutinthesynapticcleftandchewsupAch. BeforeamatureNMJforms,AchReceptors(AchR)aredistributedrandomlyacross themusclecellmembrane.Someformtinyclusterscalledhotspots.Thelifetimeof theseextrajunctionalreceptors(EJR's)isabout24hours.AstheNMJforms,EJR'sgo away,andjustundertheaxonterminal,AchR'sareverydenselypacked,andthey nowlivefor5to8days.Peoplewantedtoknowhowthisdevelopmentalprocess occurs.Somepeoplethoughtitwasdependentonelectricalimpulsesfromthe neuron,otherpeoplethoughtitwasdependentonsecretedfactors.Intheend,it requiresboth.Let'sgooverthismorethoroughly. Firstelectricalactivityforthepurposesofthefollowingexperiments,electrical activitymeanstheelectricalimpulsethattravelsdownthemotorneuron,the releaseofAch,andthedepolarizingeffectAchhasonthemusclefiber. Asthemotorneuronfires,Achbindstoitsreceptoronthemusclefiber,andcauses somedepolarization.Thisdepolarizationisnotlocallycontaineditspreads,causing widespreaddepolarizationacrossarelativelylargepartofthemusclefiber, affectingseveralnuclei(remembermusclefibersaremultinucleated).Oneofthe subunitsoftheAchRisregulatedbymembranepotential.Sothiswidespread depolarizationresultsintheinabilityofaffectednucleitoproducenewAchR's, resultinginadecreaseEJR's.However,rememberwewantincreasedAchR expressioninthenucleusdirectlyundertheneuronterminal.Fortunatelythereisa mechanisminplacetoproducenewAchR'sspecificallyinthisnucleus. Twofactorsareproducedbythemotorneuron,whichhavealocaleffectonthearea ofthemusclethatisdirectlyassociatedwiththeneuronterminus.TheyareAgrin andARIA. Agrinbindstoitsreceptor,Musk.MuskactivatesRapsyn.ActivatingRapsynhastwo effects:first,itphosphorylatesnearbyAchR's,causingthemtoaggregateandlive longer,andsecondly,itgoesdowntothenucleusandincreasestheproductionof newAchR's(overridingtheinhibitoryeffectsofthedepolarization). ARIAlikewiseactivatesitsreceptorERbB.ErbBactivatesRASwhichactivates MAPKwhicheventually,throughsomeunknownmechanism,influencesthenucleus, causingittofurtherincreaseAchRproduction. AgrinandARIAonlyaffectthenearbynucleusandreceptors,soeventually,there arealotofdenslypackedphosphorylatedAchR'sundertheaxonterminal,andno EJR's. The Neuromuscular Junction Motor Neuron Terminal ACh Agrin ARIA = NRG1 A Ch - E Muscle Extra-junctional Nucleus ACh-R PO4 PO4 M U SK ErbB Rapsyn RAS ! Vm Junctional Nucleus ACh-E ACh-R M APK ACh-R ? Howdoweknowthis?Therewereseveralexperimentsthathelpedtodiscover thesefacts.Onewasthetruncatedaxonexperiment.Ifyoucuttheaxonofamotor neuron,thenovertime,EJR'sstarttoreturn.(thissupportstheimportanceof electricalactivity).Howeverifyouleavealogaxonstumpitwilltakelongerfor EJR'storeappearthanifyouleaveashortaxonstump.(thissupportsthe importanceofsecretedfactorsalongerstumpwouldhavemorestufftosecrete thanashortstump). Nexttherewasacollarexperiment.Acholchicinecollarwasplacedaroundtheaxon, stoppingmicrotubulesfromtransportingsecretedfactorstotheterminus,but permittingelectricalimpulsestocontinueunimpeded.TheresultwasthatEJR's returned,demonstratingtheimportanceofelectricalimpulses.Thesamething happenedwhenalidocainecollarwasusedtoblockelectricalimpulsesbutnot secretedfactors.(Seenextlecture). ...
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  • Spring '10
  • Bier
  • away,andjustundertheaxonterminal,AchR'sareverydenselypacked,andthey nowlivefor5to8days.Peoplewantedtoknowhowthisdevelopmentalprocess occurs.Somepeoplethoughtitwasdependentonelectricalimpulsesfromthe, Motor Neuron Terminal, AgrinandARIAonlyaffectthenearbynucleusandreceptors,soeventually,there arealotofdenslypackedphosphorylatedAchR'sundertheaxonterminal,andno EJR, Therewereseveralexperimentsthathelpedtodiscover thesefacts.Onewasthetruncatedaxonexperiment.Ifyoucuttheaxonofamotor neuron,thenovertime,EJR'sstarttoreturn., importanceofsecretedfactorsalongerstumpwouldhavemorestufftosecrete thanashortstump

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