BIBLIOGRAFIE Neural Conduction Synaptic Transmision

7/28/2019 BIBLIOGRAFIE Neural Conduction Synaptic Transmision

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hapter 3 introduced you to the anatomy of neu-rons. This chapter introduces you to their func-tion-it is about how neurons conduct and trans-mit electrochemical signals.It begins with a descriptionofhow signalsaregenerated n resting neurons; hen, itfollows the signals as they are conducted through neu-rons and transmitted across ynapseso other neurons.

"The Lizardl'a casestudy of a patient with Parkin-son's disease,Roberto Garcia d'Orta, will help you ap-preciatewhy a knowledgeofneural conduction and syn-aptic transmission is an integral part of biopsychology.

"I have become a lizardj' hebegan. "A great lizard frozen in adark, cold, strange world."His name was Roberto Garciad'Orta. He was a

tall thin man in his sixties, ut like mostpatientswithParkinson'sisease,eappearedobemucholder hanhis actualage.''Notmanyyearsbefore,he had beenanactive, igorousbusinessman.Then t happened-notall at once,not suddenly, ut slowly, ubtly,nsidiously.Now he turned like a pieceof granite,walked n slowshufflingsteps, nd spoke n a monotonouswhisper.What hadbeenhis first symptom?A tremor.Ha dhis remorbeen isabling?"No," he said. My handsshakeworsewhen theyare doing nothing at all"-a symptom called remor-nt-rest.The other symptomsof Parkinson's isease renot quiteso benign.They can change vigorousmaninto a lizard. These nclude rigid muscles, markedpoverty of spontaneousmovements, difficulty instarting o move,and slownessn executing oluntarymovements nce heyhavebeen nitiated.The erm "reptilianstare"soften used o describethe characteristic ack of blinking and the widely

understanding eural function is the mem-potential, the difference n electricalchargebe-and he outsideof a cell.he Membrane Potential

a neuron's membrane potential, it is necessaryposition the tip of one electrode nside the neuronof another electrode outside theneuron in

ar fluid. Although the size of the extracel-electrode is not critical, it is paramount that the

4.1 - TheNeuron'sRestingMembranePotential 77

opened eyesgazing out of a motionless face,a set offeatures that seemsmore reptilian than human. Trulyalizard in the eyesof the world.What was happening in Mr. d'Orta's brain? Asmall group of nerve cells called the substantia nigra(black substance) were unaccountably dying. Theseneurons make a particular chemical neurotransmittercalled dopamine, which they deliver to another partof the brain, known as he striatum. As the cells of thesubstantia nigra die, the amount of dopamine they candeliver goesdown. The striatum helps control move-ment, and to do that normally, it needs dopamine.(Paraphrasedftorn Newton'sMadness:Further Tales f Clinical Neurol-ogybyHaroldL.I{awans, pp.53-57. NewYork Harper & Row,O Har-old Klawans. 990.)

Dopamine is not an effective treatment for Parkin-son's diseasebecause t does not readily penetrate theblood-brain barrier. However,knowledge of dopaminer-gic transmission has led to the development of an effec-tive treatment: r-dopa, the chemical precursor of dopa-mine, which readily penetrates the blood-brain barrierand is converted to dopamine once inside the brain.Mr. d'Orta's neurologist prescribed r-dopa, and itworked. He still had a bit of tremor: but his voice becamestronger,his feetno longer shuffled,his reptilian stare ad-edaway,and he was once againable to perform with easemany of the activities of daily life (e.g.,eating, bathing,writing, speaking,and even making love with his wife).Mr. d'Orta had been destined to spend the restof his lifetrapped inside a body that wasbecoming increasinglydif-ficult to control, but his life sentencewas repealed.Mr. d'Orta's story does not end here. You will readmore about him in a later chapter, and you should keephim in mind asyou read this one. His situation will re-mind you that normal neural activity is necessary ornormal psychological function. A knowledge of neuralconduction and qmaptic transmission is a major asset orany psychologist; t is a must for any biopsychologist.

''i::::::,;:'::ii :"!#tip of the intracellular electrodebe fine enough to piercethe neural membrane without severely damaging it.The intracellular electrodes are called microelectrodes;their tips are ess han one-thousandth of a millimeter indiameter-much too small to be seenby the naked eye.The RestingMembranePotentialWhen both electrode tips are in the extracellular fluid,the voltage difference between them is zero. However,when the tip of the intracellular electrode is inserted


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78 Chapter - NeuralConduction nd Synaptic ransmission

into a neuron,a steady otentialof about -70 millivolts(mV) is recorded. his ndicateshat the potential nsidethe restingneuron s about 70 mV lesshan that outsidethe neuron.This steadymembranepotential of about-70 mV is called he neuron's esting potential. In itsrestingstate,with the -70 mV chargebuilt up acrosstsmembrane, neuron s said o be polarized.

The onic Basisof the RestingPotentialWhy are resting neurons polarized?Like all salts in so-lution, the salts in neural tissue separate nto positivelyand negatively chargedparticles called ions. The restingpotential results from the fact that the ratio of negativeto positive charges s greater nside the neuron than out-side.Whythis unequal distribution of chargesoccurscanbe understood in terms of the interaction of four factors:two factors that act to distribute ionsequallythroughoutthe intracellular and extracellular fluids of the nervoussystem and two features of the neural membrane thatcounteract thesehomogenizing effects.The first of the two homogenizing factors is randommotion. The ions in neural tissue are n constant randommotion, and particles in random motion tend to becomeevenly distributed because hey are more likely to movedown their concentrationgradients han up them; that is,they are more likely to move from areasof high concen-tration to areasoflow concentration than vice versa.Thesecond actor that promotes the even distribution of ionsis electrostatic ressure.Any accumulation of charges,pos-itive or negative, n one area ends to be dispersedby therepulsion among the like charges n the vicinity and theattraction of opposite chargesconcentratedelsewhere.Despite the continuous homogenizing effects ofrandom movement and electrostatic pressure,no singleclassof ions is distributed equally on the two sidesof theneural membrane. Four kinds of ions contribute signifi-cantly to the resting potential: sodium ions (Na+), potas-sium ions (K+), chloride ions (Cl-), and various nega-tively charged protein ions. The concentrations of bothNa+ and Cl- ions are greater outside a resting neuronthan inside, whereas K+ ions are more concentrated onthe inside. The negatively charged protein ions are s1m-thesized inside the neuron and, for the most part, staythere. SeeFigure 4. 1. Bythe way,the symbols for sodiumand potassium were derived from their Latinnames: na-trium (Na+) and kalium (K+), respectively.TWo properties of the neural membrane are respon-sible for the unequal distribution of Na+, K+, Cl-, andprotein ions in resting neurons. One of thesepropertiesis passive; hat is, it does not involve the consumption ofenergy.The other is activeand does nvolve,theconsump-tion of energy. The passiveproperty of the neural mem-brane that contributes to the unequal disposition of Na+,K+, C1-,and protein ions is its differential permeabilityto those ions. In resting neurons, K+ and Cl- ions pass

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Nai

ct-

ln itsresting tate,more Na+and Cl-ionsareoutsidehe neuron han nside, nd more K+ onsand negativelyharged roteinonsare nside he neuronthan outside.

readily through the neural membrane,Na+ ions pass hrough it with difficulty,and the negatively chargedprotein ionsdo not passthrough it at all. Ions passthrough the neural membrane at spe-cializedpores called ion channels, eachtlpe of which is specialized or the pas-sageof particular ions.

In the 1950s, he classicexperiments of neurophysi-ologists Alan Hodgkin and Andrew Huxley providedthe first evidence that an energy-consuming processisinvolved in the maintenance of the resting potential.Hodgkin and Huxley began by wondering why the highextracellular concentrations of Na+ and Cl- ions andthe high intracellular concentration of K+ ions werenot eliminated by the tendency for them to move downtheir concentration gradients to the side of lessercon-centration. Could the electrostatic pressure of -70 mVacross the membrane be the counteracting force thatmaintained the unequal distribution of ions? To answerthis question, Hodgkin and Huxley calculated for eachof the three ions the electrostatic charge that would be

ON THECDThe onChonnelsmod-ule llustratesthe ocationsand unctions fdifferent ypesofionchannels.


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required to offset the tendency or them to move downtheir concentration gradients.

For Cl- ions, this calculatedelectrostatic hargewas-70 mV the same as he actual restingpotential. Hodg--


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80 Chapter * NeuralConduction nd Synaptic ransmissionfEElmD TheFactorsResponsibleor Maintaining he Differencesn the lntracellularandExtracellular oncentrations f Na+,K+,and Cl- ons n RestingNeurons..1..,...,.*a.t,.'..',..,.l]:..r{;,1.:n::tina,to.,oa,eriif,,lin*,,th9.n!nioni,,!r:'notrr,lirrc,rr1shti6!..oi:xa+,,.ions.,outsidehe neuronulq ah: negativentemal esting otential f -70 mV.However,hemembranes resistanto the passive iffusion f rui*, and hethusable o maintainhe highexternal oncentrationf Na+ onsbythesameslow rateas hey love in.

: " r ' : j i ' : , U il i r ' ; - ; l i - ,a i f r l i '

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.cl.:. There s.littleesistance_inhe neural "rnbrun" to the passagef Cl- ons.Thus,

:i::r::tj:::r:.:],:ri:ti.:,,,i.rrl .i::,,i l l i lK+ ons end o moveout of the neuronbecause f their high nternal oncentration,althoughhis endencys partially ffsetby he nternal egative otential. espitehetendencyor the K+ ons o leavehe neuron,hey do soat a substantialatebecausethe membrane ffers ittle esistanceo their passage.omaintain he high nternalc.oncentrationf K+ ons,mechanismsn he cellmembrane umpK+ ons ntoneurons tthe same ateas heymoveout.There s ittle esistancen the neuralmembraneo the passgeof cl - ions.Thus, l- ionsare readilyorcedout of theneuronby he negativenternal otential.u chloride onsbegin o accumulaten theoutside,here san ncreasedendencyor them o move

ON THECDlonic Basisof theRestingMem-brone Potentiolmodule oreviewhe rolethat K+ onsandNa+ ons la y ndeterminingherestingmem-brane otential.egin o accumulaten theoutside,here san ncreased

equilibrium ccurs t -70 mV.

down heirconcentrationradient ack nto he neuron.When he point s reached herethe electrostaticressureor Cl- ons o moveout of the neuron s equal o thetendencyfor th.emo moveback n. hedistribution f Cl- ons s held n equilibrium. hispointof

them are not independentprocesses. uch on transportis performed by energy-consumingmechanisms n thecell membrane that continually exchange hree Na+ ionsinside the neuron for two K+ ions outside.These rans-port mechanisms are commonly referred to assodium-potassium pumps.

Table4.1 summarizes he major factors hat are re-sponsible for maintaining the differences between the

intracellular and extracellular concentrations of Na+,K+,and Cl- ions in resting neurons. These differences plusthe negative charges of the various protein ions, whichare trapped inside the neuron, are argely responsibleforthe restingmembrane potential.Now that you understandthesebasic properties ofthe resting neuron, you are prepared to consider howneurons respond o input.

(:*#,.^\ffi! GemerationndeonductEenf PostsyrrptiaotentialsF?When neurons fire, they release rom their terminal but-tons chemicals called neurotransmitters, which diffuseacross the synaptic clefts and interact with specializedreceptor molecules on the receptive membranes of thenext neurons in the circuit. When neurotransmittermolecules bind to postsynaptic receptors, they typicallyhave one of two effects,depending on the structure ofboth the neurotransmitterand the receptor n question.They may depolarize the receptivemembrane (decreasethe resting membrane potential, from -70 to -67 mVfor example) or they may hyperpolarize it (increase heresting membrane potential, from -70 to -72 mV, forexample).

Postsynaptic depolarizations are called excitatorypostsynaptic potentials (EPSPs) because,as you willsoon learn, they increase he likelihood that the neuronwill fire. Postsynaptic hyperpolarizations are called in-

hibitory postsynapticpotentials (IPSPs)becauseheydecreasehe likelihood that the neuron will fire. BothEPSPs nd PSPs regraded esponses. hismeans hatthe amplitudes f EPSPsnd IPSPs reproportional othe ntensityof the signals hat elicit them:Weaksignalselicit small postsynapticpotentials,and strong signalselicit argeones.EPSPsand IPSPs ravel passivelyfrom their sitesof generationat slmap-ses, suallyon the dendrites r cellbody,in much the same way that electricalsignals ravel through a cable.Accord-ingly, he transmission f postsynapticpotentialshas two important charac-teristics. irst, t is rapid-so rapid hatit canbe assumedo be instantaneousfor mostpurposes.t is mportantno t

ON THECDTovisualizethe nteractionsbetween nputsfrom nhibi-toryneurons ndthose rom ex-citatory eurons,visit he /nferoc-tionsbetweenEPSPsnd IPSPsmodule.


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to confusehe duration of EPSPs nd IPSPs ith theirrateof transmission; lthough he duration of EPSPsand IPSPs ariesconsiderably,ll postsynaptic oten-tials,whetherbrief or enduring,are ransmittedat great

Integration f Postsynaptic otentials nd Generation f ActionPotentials 81speed.Second, he transmission of EPSPsand IPSPs sdecremental:EPSPsand IPSPs decrease n amplitudeas they travel through the neuron, just as a sound wavegrows fainter as t travels through air.

-_

Wj $mtegratlonf FostsynapticoteniatrslndG*merationf AsEss?*&*mBefsThe postsynaptic potentials created at a single s)rylapsen'pically have little effect on the firing of the postsyn-aptic neuron. The receptive areasof most neurons arecoveredwith thousandsof slmapses, nd whether or nota neuron fires is determined by the net effect of theiractivity. More specifically, whether or not a neuron firesdepends on the balance between the excitatory and in-hibitory signals reaching its axon. Until recently, it wasbelieved that action potentials were generated at theaxon hillock (the conical structure at the junction be-fween the cell body and the axon), but they are actuallygenerated n the adjacentsection ofthe axon.

The gradedEPSPsand IPSPscreatedby the actionof neurotransmitters at particular receptive sites on aneuron's membrane are conducted nstantly and decre-mentally to the axon hillock. If the sum of the depolar-izations and hyperpolarizations reaching the section ofthe axon adjacentto the axon hillock at any time is suffi-cient to depolarize the membrane to a evel referred to asits threshold of excitation-usually about -65 mV-anaction potential is generatednear the axon hillock. Theaction potential (AP) is a massive momentary-lastingfor I millisecond-reversal of the membrane potentialfrom about -70 to about +50 mV. Unlike postsynapticpotentials,action potentials are not graded responses;their magnitude is not related in any way to theintensityof the stimuli that elicit them. To the contrary, they areall-or-none responses; that is, they either occur to theirfull extent or do not occur at all. SeeFigure 4.3 for anillustration of an EPSP, n IPSP, nd an AP.

(milliseconds)

In effect, each multipolar neuron adds together allthe graded excitatory and inhibitory postsynaptic po-tentials reaching its axon and decides o fire or not to fireon the basisof their sum. Adding or combining anum- Time (mill iseconds)ber of individual signals nto one over- oN THE Dall signal s calledntegration. Neuronsintegratencoming signals n two ways:overspace nd over ime.Figure .4 onpage 2 llustrateshethreepossible ombinations f spatialsummation. It showshow local EPSPsthat are producedsimultaneously ndifferent parts of the receptivemem-branesum o form a greater PSR ow

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niVisit heSummotion fEPSPs odulefor an llustrationof how emporalsummationrspatial umma-tion of EPSPscanelicit n ac-tion potential.


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Th e hreepossible

Excitatory

Figure 4.5 on page83 illustrates em-poral summation. It showshow postsyn-aptic potentialsproduced n rapid succes-sion at the samesynapsesum to form agreater signal. The reason that stimula-tions of a neuron can add together overtime is that the postsynaptic potentialsthey produce often outlast them. Thus, ifa particular synapse s activatedand thenactivatedagain before the original post-synaptic potential has completely dissi-pated, the effect of the second stimuluswill be superimposed on the lingeringpostslmaptic potential produced by thefirst. Accordingly, t is possible or a briefsubthreshold excitatory stimulus to fire aneuron if it is administered wice in rapidsuccession.n the sameway,an inhibitorys1.ltapseactivated twice in rapid succes-sion can produce a greater PSP han thatproduced by a singlestimulation.Each neuron continuously inte-gratessignals over both time and spaceas it is continually bombarded with

Twosimultaneous PSPsA Stimulated

=E(EcooCLoc,9troE

sum o producea greaterEPSPB Stimulated A+ B Stimulated

A + C Stimulatedr:Trr:::::,r::-:-::Il llt::.i:ti::t]:t]:l]l':,triil.,]r:r.r:i:.i'r,:lj

-65-74-75

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EPSPcancel each other outC Stimulated-65-7 i-75

stimuli through the thousands of spr-apses covering its dendrites and cellbody. Remember that, although sche-matic diagramsof neural circuitry rarelyshow neuronswith more than a fewrep-resentativeslnaptic contacts, most neu-rons receive housandsof such contacts.The location of a synapse on aneuron's receptivemembrane has longbeen assumed o be an important fac-tor in determining its potential to influ-ence he neuron's firing. BecauseEPSPsand IPSPsaretransmitted decrementally, ynapses ear the axon trig-ger zone havebeen assumedto have the most influenceon the firing of the neuron (seeMel, 2002). However, ithas recentlybeendemonstrated hat some neuronshave

a mechanismor amplif.ingdendritic ignalshat origi-nate ar from theircellbodies; hus,al l dendriticsignalsreachinghe cellbody of sucha neuronhavea similaramplitude, egardlessf where hey originate Williams& Stuart,2002,2003).In someways, he firing of a neuron s like the fir-ing of a gun.Both areall-or-noneeactionsriggered ygraded esponses.s a trigger s squeezed,t graduallymoves back until it causes he gunto fire; as a neuron is stimulated,it becomes less polarized until thethresholdofexcitation is reachedand firing occurs.Fur-thermore, the firing of a gun and neural firing arebothall-or-noneevents.ust assqueezing trigger harderdoesnot make the bullet travel fasteror farther, stimulating aneuron more intensely does not increase he speed oramplitude of the resultingactionpotential.

ON THECDFormoreabouthow heinteractionsbetuveenPSPsand PSPseter-minewhether rnota neuron il lfire, akea lookatthe ntegrc-tion of Postsyn-optic Potentialsmodule.

'-::F-l-::n-::7! -.= TwosimultaneousPSPs um o produce greaterPSPCStimulated DStimulated C+DStimulated-65f-----l -65---------l -6sf----l-;:.---J;:.-_1;: /.JA simultaneousPSPandA Stimulated


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/'-..---.( , ; \qdfu*\ eonductisnf Aetlon o*s*t*alsru!iT"Freonie Basisof ActEtlm otentiaEsHow are action potentials produced, and how are theyconductedalong he axon?The answer o both questionsis basically the same: through the action of voltage-activated ion channels-ion channels hat open or closein responseo changes n the level of the membranepo-tential (seeMcCormick, 1999).

Recall hat the membrane potential of a neuron atrest s relativelyconstant despite he high pressureactingto drive Na+ ions into the cell. This is because he rest-ing membrane s relatively impermeable o Na+ ons andbecause hose few that do pass n are pumped out. Butthings suddenly change when the membranepotential

4.4 .* - Conduction f Action Potentials 83

@ Thetwopossib lecombinationsf emporal ummation.

of the axon is reduced to the threshold of excitation. Thevoltage-activated sodium channels in the axon mem-brane open wide, and Na+ ions rush in, suddenly driv-ing the membrane potential from about *70 to about+50 mV. The rapid change n the mem-brane potential that is associatedwiththe influx of Na+ ions then triggers theopeningof voltage-activated otassiumchannels.At this point, K+ ions nearthe membrane are driven out of the cellthrough these channels-first by theirrelatively high internal concentrationand then, when the action potential is

Excitatory

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ogo.u.E.gtrooCLotr(Elltro=

Two EPSPs licited n rapidsuccession um oproducea largerEPSP-65-70

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ON THECDlne uen-eration of theAdion Potentiolmodule xplainsthe hresholdof activationfvoltage-activatedionchannels.


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Th eoPenrng ng of voltage-activatedodiumandpotassiumchannelsuring he hreephases f theactionpotential:rising hase,epolarization,ndhyperpolarization. Sodium

close

Potassiumchannelsstart oclose

The refractory period is responsible for two impor-tant characteristicsofneural activity. First, it is responsi-ble for the fact that action potentialsnormally travel along;xons in only one direction. Because he portions of anixon over which an action potential has ust traveledareleft momentarily refractory, an action potential cannotreversedirection. Second, he refractory period is respon-sible for the fact that the rateofneural firing is relatedtothe intensity of the stimulation. If a neuron issubjected oa high levelof continual stimulation, it firesand then firesagain assoon as ts absolute refractory period is over-amaximum of about 1,000 times per second. However, ifthe level of stimulation is of an intensity just sufficient tofire the neuron when it is at rest, he neuron does not fireagain until both the absoluteand the relative refractoryperiods have un their course. ntermediate levelsof stim-ulation produce intermediate ratesof neural firing.AxonalConductionof Action PotentialsThe conduction of action potentials along an axon dif-fers from the conduction of EPSPsand IPSPs n two im-portant ways.First, the conduction of action potentialsalong an axon is nondecremental;action potentials donot grow weaker as they travel along the axonal mem-brane. Second, action potentials are conducted moreslowly than postslmaptic potentials.The reason for these two differences s that the con-duction of EPSPs nd IPSPs s passive,whereashe axonalconduction of action potentials is largely active.Once anaction potential has been generated, t travels passivelyalong the axonal membrane to the adjacent voltage-activated sodium channels, which have yet to open.The arrival of the electrical signalopens these channels,thereby allowing Na+ ions to rush into the neuron andgeneratea full-blown action potentialon this portion ofthe membrane.This signal sthen conductedpassivelyothe next sodium channels, where another action poten-

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-Sodium channelsPotassiumchannelsopenchannelsopen

near its peak,by the positive internal charge.After about1 millisecond, the sodium channels close.This marksthe end of the rising phase of the action potential andthe beginnin g of repolarization by the continued effluxof K+ ions. Once repolarization has been achieved,thepotassium channelsgradually close.Because hey closegradually, too many K+ ions flow out of the neuron, andit is left hyperpolarized for abrief period of time. Figure4.6 illustrates the timing of the opening and closing ofthe sodium and potassium channels during an actionpotential.The number of ions that flow through the mem-brane during an action potential is extremely small inrelation to the total number inside andaround the neuron. The action poten-tial involves only those ions right nextto the membrane. Therefore, a singleaction potential has little effect on therelative concentrations of various ionsinside and outside the neuron, and theresting ion concentrations next to themembrane are rapidly reestablishedbythe randommovement f ions.The sodium-potassiumpump playsonly a minor role in the reestablishmentfthe esting otential.RefractoryPeriodsTheres a briefperiodof about1 o 2 millisecondsfterthe initiation of an action potential during which it isimpossibleo elicit a second ne.This period s calledthe absolute efractoryperiod. The absolute efractoryperiod is followedby the relative refractory period-the period during which it is possibleo fire the neuronagain, ut onlyby applyinghigher-than-normalevelsofstimulation.The end of the relative efractoryperiod isthe point at which the amount of stimulationnecessaryto f ire a neuronreturns o baseline.

ON THECDFora de-tailedreviewofthe onicbasis faction oten-tials, ee helonic Basisof theAdion Potentiolmodule.


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tial is actively triggered. Theseevents are repeatedagainand again until a full-blown action potential is triggeredin all the terminal buttons (Huguenard,2000).However,because here are so many ion channels on the axonalmembrane and they are so close together, it is usual tothink of axonal conduction asa single wave of excitationspreading actively at a constant speed along the axon,rather than asa seriesof discrete events.The wave of excitation triggered by the generationofan action potential near the axon hillock also spreadsback through the cell body and dendrites ofthe neuron.Aithough little is yetknown about the functions of thesebackward action potentials, they are currently the sub-.iectof intensive nvestigation.The following anilogy may helpyou appreciatehe major characteris-tics of axonalconduction.Considerarow of mousetrapson a wobbly shelf, all of them set andready to be triggered. Each trap stores energy by hold-ing back its striker against the pressureof the spring, inthe same way that each sodium channel stores energy byholding back Na+ ions, which areunder pressure o movedown their concentration and electrostaticgradients ntothe neuron. When the first trap in the row is triggered, hevibration is transmitted passively hrough the shelf, andthe next trap is sprung-and so on down the line.The nondecremental nature of action potentialconduction is readily apparent from this analogy; thelast trap on the shelf strikes with no less ntensity thandid the first. This analogy also illustrates the refractoryperiod: A trap cannot respond again until it has beenreset, ust as a section of axon cannot fire again until ithasbeen repolarized.Furthermore, the row of traps cantransmit in either direction, just like an axon. If electricalstimulation of sufficient intensity isapplied to the termi-nal end of an axon, an action potential will be generatedand will travel along the axon back to the cell body; thisis called antidromic conduction. Axonal conduction inthe natural direction-from cell body to terminal but-tons-is called orthodromic conduction.

Conductionn MyelinatedAxonsIn Chapter 3, you learned that the axons of many neu-rons are insulated from the extracellular fluid by seg-ments of fatty tissue called myelin In myelinated axons,ions can pass hrough the axonal membrane only at thenodes of Ranvier-the gaps between adjacent myelinsegments. ndeed, in myelinatedaxons, sodium channelsare concentrated at the nodes of Ranvier (Salzer,2002).How, then, are action potentials transmitted in myelin-ated axons?

When an action potential is generated in a myelin-ated axon, the signal is conducted passively-that is, in-stantly and decrementally-along the first segment ofmyelin to the next node of Ranvier. Although the signal

4.4 - Conduction f Action Potentials 85

is somewhat diminished by the time it reaches hat node,it is still strong enough to open the voltage-activatedsodium channels at the node and to generate anotherfull-blown action potential. This action potential is thenconducted passively along the axon to the next node,where another full-blown action potential is elicited,and so on.Myelination increases he speedof axonal conduc-tion. Because onduction along the myelinated segmentsof the axon is passive, t occurs instantly, and the signalthus "jumps" along the axon from node to node. Thereis, of course,a slight d,elayat each node of Ranvierwhilethe action potential is actively generated,but conductionis still much faster in myelinated axons than in unmy-elinated axons, in which passiveconduction plays a lessprominent role. The transmission of action potentials inmyelinated axons is called saltatory conduction (saltaremeans to skip or jump").

The Velocityof AxonalConductionAt what speed are action potentials conducted alongan axon? The answer to this question depends on twoproperties of the axon. Conduction is faster in large-diameter axons, and-as you have just learned-it isfaster in those that are myelinated. Mammalian motorneurons (neurons that synapse on skeletal muscles) arelarge and myelinated; thus, some can conduct at speedsof 100 meters per second (about 224 miles per hour).In contrast, small, unmyelinated axons conduct actionpotentialsat about I meter per second.There is a misconception about the velocity of motorneuron action potentials in humans. The maximum ve-locity of motor neuron action potentialswas found to beabout 100meters per second n catsand was hen assumedto be the same n humans: It is not. The maximum velocityof conduction in human motor neurons s about 60 metersper second Peters Brooke,1998).

Conduction n Neuronswithout AxonsAction potentials are the meansby which axons conductall-or-none signals nondecrementally over relativelylong distances.Thus, to keepwhat you have ust learnedabout action potentials in perspective, it is importantfor you to remember that many neurons in mammalianbrains do not haveaxons and thus do not display actionpotentials. Neural conduction in these interneurons istypically by graded, decrementally conducted potentials(]uusolaet al., 1996).

TheHodgkin-HuxleyModel and theChangingView of DendriticFunctionThe precedingaccountof neural conduction is basedheavily on the Hodgkin-Huxley model, the theory


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86 Chapter4 - Neural ConductionandSynapilcTransmission

proposed y Hodgkin and Huxley n theearly 1950sseeHuxley,2002).Although this theorydoesa good ob ofaccountingor the fundamental haracteristicsf neuralconduction, t fails o explainmanycomplexities f neu-ral conduction hat havebeensubsequently iscovered(seeMeunier& Segev, 002).Arguably,he greatest hortcomingof the Hodgkin-Huxleymodel s its failure o account or three recentlydiscovered bilitiesof dendrites,which have ong beenassumedo be merelypassive onductorsof postsynap-tic potentialsseeHiiuser, pruston, Stuart,2000).hefirst of these ecentdiscoveriess that somedendritesarecapable fgeneratingactionpotentials,whichcanbeac-tively conductedaway rom the siteof generationn ei-therdirection e.g., hen,Midtgaard, Shepherd,997).The second nd hird discoveriesoth involvedendritic

You have learned in this chapter how postsynaptic po-tentials are generated on the receptive membrane of aresting neuron, how these graded potentials are con-ducted passively to the axon, how the sum of thesegraded potentials can trigger action potentials, and howtheseall-or-none potentials are actively conducted downthe axon to the terminal buttons. In the remaining sec-tions of this chapter,you will learn how action potentialsarriving at terminal buttons trigger the releaseof neu-rotransmitters into synapses and how neurotransmit-ters carry signals to other cells. This section provides anoverview of five aspectsof synaptic transmission: (l) thestructure of slmapses;2) the synthe-sis,packaging, nd transportof neu-rotransmittermolecules;3) the releaseof neurotransmittermolecules; ) theactivationof receptorsby neurotrans-mitter molecules; nd (5) the reuptake,enzymaticdegradation,and reryclingof neurotransmittermolecules.Structureof SynapsesMost communicationamong neuronsoccursacross ).napsesuch as he oneillustrated in Figure 4.7. Neurotrans-mitter molecules are released rombuttons nto synapticclefts,where heyinduce EPSPs r IPSPs n other neu-rons by binding to receptorson theirpostsynapticmembranes. he synapsesfeatured n Figure 4.7 are axodendriticsynapses-synapsesf axon terminalbuttonson dendrites.As vou have ust

www. ablo ngman.com/ pinel6e

spines, nodulesof various shapes hat are locatedonthe surfacesof many dendrites(seeYuste,Majewska,& Holthoff, 2000) and are the sitesof most excitatoryqmapsestlpically onesynapseer spine) n the maturemammalianbrain. Thesecond iscoverysthat dendrit-ic spinescompartmentalizedendrite; hat is, hey tendto keeppostsynaptic hemicalchanges estricted o theimmediate reaof the synapseSegal, 001).The thirdis that dendritic spineschange apidly (within minutesto hours) in shapeand number in responseo neuralstimulation Hering& Sheng,2001; asai t a1.,2003).It is not yet well understoodhow thesenewly rec-ognizeddendritic capabilities ffectneuralconduction.Still, heir discoverywill surelyprove o be acritical steptoward mprovedunderstanding f neuralconduction.

learned,manyexcitatorys).napseserminateon dendrit-ic spinesseeFigure3.31).Alsocommonareaxosomaticsynapses-synapsesf axon terminal buttons on somas(cellbodies).Although axodendritic and axosomaticsynapsesare he rnostcommon synapticarrangements,here areseveral thers Shepherd& Erulkar, 1997).Forexample,therearedendrodendritic ynapses,hich are nterestingbecausehey are often capable f transmission n eitherdirection; and there areaxooxonal ynapses,hich areinterestingbecause omeof them mediatepreslmapticinhibition(seeWu& Saggau,997). resynapticinhibi-tion is comparedwith postsynaptic nhibition in Fig-ur e4.8on page 8.The synapses epicted n Figure 4.7 arc directedsynapses-synapsest which the site of neurotransmit-ter releaseand the site of neurotransmitter eceptionare n closeproximity.This is a common arrangement,but there are also many nondirectedsynapsesn themammaliannervoussystem.Nondirectedsynapses resynapses t which the site of releases at somedistancefrom the siteof reception.One ype of nondirected 1n-apse s depicted n Figure4.9 on page90. In this typeof arrangement,neurotransmitter moleculesare re-leasedrom a series fvaricositiesalong he axonand tsbranchesand thus are widely dispersedo surroundingtargets.Because f their appearance,hesesynapses reoftenreferred o asstring-of-beadsynapses.Synthesis,Packagin&and Transportof NeurotransmitterMoleculesThere are two basic categoriesof neurotransmitter mol-ecules:small and large. The small neurotransmitters are

ON THECDthe SynapticTransmissionanimation.Seesynaptictransmissionnaction.

ON THECDTheAAionat the Synopsemodulepresentsdiagrams,explanations,and exercisesthatwill helpyouunderstandndrememberhemechanismsfsynapticunction.


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l ,{icrotubules

Synaptic.restctes

Synapticcleft

Golg icomprex

Mitochondrion

Dendrit icspinePresynapticmemorane

of several ypes; arge neurotransmitters are allpeptides.Peptidesare amino aci d chains hat are composedof 10or fewer amino acids; n effect, hey are shortproteins.They may be small for proteins, but they are large forneurotransmitters.

Small-molecule neurotransmitters are typicallysynthesized in the cytoplasm of the terminal buttonand packaged n synaptic vesicles by the button's Golgicomplex (seeBrittle & Waters, 2000). Once filled withneurotransmitter, he vesicles re stored n clustersnextto the presynapticmembrane. In contrast,peptide neu-rotransmitters, ike other proteins,are assembledn thecytoplasm of the cell body on ribosomes; hey are thenpackaged n vesiclesby the cell body's Golgi complexand transportedby microtubules o the terminal buttonsat a rate of about 40 centimeters per day. The vesiclesthat contain large-moleculeneurotransmittersare argerthan those that contain small-molecule neurotransmit-ters, and they do not congregate as closely as the othervesicles o the presynapticmembrane.

It may have escaped our notice that the button il -lustrated in Figure 4.7 contains synaptic vesicles f twosizes. his means hat it contains wo neurotransmitters:a peptide neurotransmitter in the larger vesiclesand asmall-moleculeneurotransmitter in t he smaller vesicles.It was once believed that each neuron slrrthesizes and

4.5 .. * Synaptic ransmission:hemical ransmissionf Signalsro m On eNeuron o Another 87

Theanatomyof a typical ynapse.

Postsynapticmembrane

releases nly one neurotransmitter,but it is now clearthat many neurons contain two neurotransmitters-asituation that is referred to as coexistence. So far, al-most all documented casesof coexistencehave involvedone small-molecule neurotransmitter and one peptideneurotransmitter.

Release f NeurotransmitterMoleculesExocytosis-the process of neurotransmitter release-is illustrated n Figure4.10 on page90 (seeZucker,Kull-man, & Bennett,1999). Ahen a neuron isat rest,synapticvesicles hat contain small-molecule neurotransmitterscongregatenext to sectionsof the preslmaptic mem-brane that are particularly rich in voltage-activatedcal-cium channels.When stimulated by action potentials,thesechannelsopen, and Ca2+ ons enter he button. Theentry of the Caz+ ons causeshe synapticvesicles o fusewith the presynapticmembrane and empty their con-tents into the spraptic cleft (seeRettig & Neher, 2002).The exocytosis f small-moleculeneurotransmittersdiffersfrom the exocftosisof peptideneurotransmittersin one important respect.Small-molecule neurotrans -mitters are ypically released n a pulseeach ime an ac-tion potential triggersa momentary influx of Ca2+ onsthrough the presynapticmembrane; n contrast,peptide


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88 Chapter NeuralConduction nd Synaptic ransmission

\_IggEEl.8_, Postsynaptican dpresynapticnhibit ion.

PresynapticInhibition

neurotransmittersare ypically released radually n re-sponse o general ncreases n the level of intracellularCa2+ ons, such asmight occur during a general ncreasein the rateof neuron i r ine.

r ,. ' : . r .. t : t , | .. , ",, , ,_t.1,: ., i : : . ' : : ,

Once released, eurotransmittermoleculesproduce sig-nals n postsynapticneuronsby binding to receptors nthe postsynapticmembrane. Each receptor is a proteinthat containsbinding sites or only particularneurotrans-mitters; hus, a neurotransmittercan nfluenceonly thosecells hat have receptors or it. Any molecule that binds toanother s referred o as t s ligand, and a neurotransmit-ter is thus said to be a ligand of its receptor.

theexcitatoryneuron ynapsing

ExcitatorysynapseExcitatorysynapse

In presynapticnhibition,B inhibits heexcitatory ffectsofA on C by partially epolarizinghe buttonof A, so thatactionpotentialsraveling ownA produce smaller hange n hemembrane otential nd hus eleasees sneurotransmitterontoC. Notice hatpresynapticnhibit ion ccurs n theabsence f inhibitory eurotransmittersr lPSPs.

It was initially assumed that there is only one typeof receptor for each neurotransmitter,but this has notprovedto be the case. s more receptorshavebeen den-tified, it has become clear that most neurotransmittersbind to severaldifferent typesofreceptors. The differenttypes of receptors o which a particular neurotransmit-ter can bind are called the receptor subqpes for thatneurotransmitter. The various receptor subtypes for aneurotransmitterare ypically located n different brainareas, nd they typically respond o the neurotransmitterin different ways (seeDarlison & Richter, 1999). Thus,one advantageof receptor subtypes s that they enablea neurotransmitter to transmit different kinds of mes-sageso differentparts ofthe brain.The binding of a neurotransmitter to one of its re-ceptor subtypes can influence a postsynaptic neuron

In postsynapticnhibition,inhibitseffects f A or anyother xcitatoryon C by hyperpolarizing.


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Synaptic ransmission:hemical ransmissionf Signalsrom One Neuron o Another 89

@ Nondirectedneurotransmitterelease.om eneurons eleaSe eurotransmittermolecules iffuselyrom varicositiesalong he axonand ts branches.

times. The metabotropic receptoris attached o a por-tion of the signalprotein outside he neuron; the G pro-tein is attached o a portion of the signalprotein insidethe neuron.r'Vhen a neurotransmitter binds to a metabotropicreceptor,a subunit of the associatedG protein breaksaway.Then, one of two things happens, depending onthe particular G protein: The subunit may move alongthe insidesurfaceof the membrane and bind to anearbyion channel, hereby nducing an EPSPor IPSP;or it maytrigger the s1'nthesisof a chemical called a second mes-senger (neurotransmittersare considered obe the irstmessengers).nce created,a second messengerdiffusesthrough the cytoplasm and may influence the activitiesof the neuron in a variety of ways(Neves,Ram, & Iyen-gar,2002)-for example, t may enter the nucleusandbind to the DNA, thereby nfluencing geneticexpression(seeNoselli & Perrimon, 2000). Thus, a neurotransmit-ter's binding to a metabotropic receptor canhave radi-cal, ong-lastingeffects.One type of metabotropic receptors-autorecep-torc-waftants special mention (seeParnas et a1.,2000).Autoteceptots are metabotropic receptors that havetwo unconventional characteristics: They bind to theirneuron's own neurotransmitter molecules; and they are

in one of two fundamentally different ways, dependingon whether the receptor is ionotropic or metabotropic(Heuss& Gerber,2000;Waxham, 1999).Ionotropic re-ceptors are those receptors hat are associatedwith li -gand-activated on channels;metabotropic receptorsare those receptors hat are associatedwith signal pro-teins and G proteins (guanosine-triphosphate-sensitiveproteins)- see Figure 4. 1 on page91.

\Arhen neurotransmittermoleculebinds to an ono-tropic receptor, he associatedon channelusually opensor closes mmediately, thereby inducing an immediatepostsynaptic potential. For example, n some neurons,EPSPs depolarizations)occur because he neurotrans-mitter opens sodium channels, hereby increasing theflow of Na+ ons into the neuron. In contrast, PSPs hy-perpolarizations)often occur because he neurotrans-mitter opens potassium channelsor chloride channels,thereby ncreasing he flow of K+ ions out of the neuronor the flow of Cl- ions into it, respectively.Metabotropic receptors are more prevalent thanionotropic receptors,and their effectsare slower to de-ve1op, longer-Iasting, more diffuse, and more varied.There are many different lcrnds of metabotropic recep-tors, but each s attached o a signalprotein that windsits way back and forth through the cell membrane seven


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90 Chapter - NeuralConduction nd Synaptic ransmission *tw tn"ab a n gman.com/pinel6e

neurotransmittersappearso be the transmissionof rap-id, brief excitatory or inhibitory signals o adjacent cells;and the function of peptideneurotransmittersappearsobe the transmissionof slow,diffuse, ong-lastingsignals.Reuptake,EnzynraticDegradaticln"nd kecyelingIf nothing intervened, a neurotransmitter moleculewould remain active in the synapse, n effect cloggingthat channel of communication. However, wo mecha-nisms terminate synapticmessages nd keep that fromhappening. These two message-terminating mecha-nisms are reuptake and enzymatic degradation (seeFigure .12onpageg2).

Reuptake s the more common of the two deacti-vating mechanisms.The majority of neurotransmitters,

ffigPresynapticmembrane :: 'Postsynapticj membrane{Ki '{lA l..q

Schematicndphotographicllustrationsf exocytosis(Thephotomicrograph as reproducedrom J. E.Heuseret al., ournolof CellBiology,1979'81,275-3oo, y copyright ermissionf TheRockefellerniversitv ress.)

located on the presynaptic, rather thanthe postsyraptic, membrane. Their usualfunction is to monitor the number ofneurotransmitter molecules in the syrr-apse, o reduce subsequentreleasewhenthe levelsare high, and to increasesubse-quent releasewhen they are ow.Differencesbetween small-moleculeand peptide neurotransmitters in pat-

ON THECDTheReviewof SynopticTransmissionmodule akesan n-depthookat hedifferentstages f synap-tic ransmission.

terns of releaseand receptorbinding suggest hat theyservedifferent unctions.Small-molecule eurotransmit-ters tend to be released nto directed slrlapsesand to ac-tivateeither onotropic receptorsor metabotropic recep-tors that actdirectlyon ion channels.n contrast,peptideneurotransmitters end to be released iffuselyand bindto metabotropic receptors hat act through secondmes-sengers.Consequently, he function of small-molecule


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4. 5 Synaptic ransmission:hemical ransmissionf Signalsrom OneNeuron o Another 91

An onotropicReceptor*G* * ,r " lonNeurotransmitter-" e; lonotropicreceptor

Closedio nchannel

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once released, re almost immediately drawn back intothe preslmapticbuttons (seeClementset al.,1992).In contrast, other neurotransmittersare degraded(brokenapart) n the spapse by theaction of enrymes-proteins that stimulateor inhibit biochemical reactionswithout being affectedby them. For example,acetylcho'line, one of the few neutotransmitters for which enzy-matic degradation is the main mechanism of slmapticdeactivation, is broken down by the enzyme acetylcho-linesterase.

Someneurotransmitteroleculesind o receptorsn on-channels'Whena neurotransmitteroleculeindso an onglropic6ceptor,thechannelpens as n hi s ase) rcloses,herdby lterjngheflowof ons ntoor outof heneuron.A Metabotropic eceptor

s*tr"F

Someneurotransmitteroleculesind o receptorsnmembrffi ;signal roteins,hich re inkedo G proteins. hena neurotra*ffifttermoleculebinds o a metabotropic eceptor, subunitof theG proteinbreaksof f into he neuronand eitherbinds o an ionchannelor stimulateshe synthesis f a secondmessenger'WIII neuroscienceproveo be amisnomer?Anybody for "gliascience"?

.,i..;r. rr: ,i-;..it;fi Interest n gap unctions has recentlybeen rekindled. Gap unctions arenarrow spaces etweenadjacent neurons that arebridged by fine tubular chan-nels that contain cltoplasm. Consequently, he qtoplasmis continuous, allowing electrical signals and small mol-ecules o passreadily from one neuron to the next. Gapjunctions are sometimescalled electricalsynapses.

Gap junctions are commonplace in invertebratenervous svstems, ut their existencewas more difficult

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@ tonotropicandmetabotropiceceptors.

Terminal buttons are models of effi-ciency. Neurotransmitter molecules thathave been released nto the synapseortheir breakdownproductsaredrawn backinto the button and recycled, egardless fthe mechanism of their deactivation. Eventhe vesicles are rerycled from the presyn-apticmembrane Harataet a1.,2001).

6HF*4 Frrlrg.tl--ii:r,irt,*,tedSyr* wp*Fri :1i;':.-1i; 1; lr'p*s 6 t $BOnce overlooked as playing merely sup-portive roles in the nervous system,glialcells have recently been thrust to centerstage by a wave of remarkable findings(Haydon, 2001; Newman, 2003; Ran-som, Behat, & Nedergaard,2003). Forexample, astrocyteshave been shown toreleasechemical transmitters,to containreceptorsfor neurotransmitters,to con-duct signals,and to participate in neu-rotransmitter reuptake (seeOliet, Piet, &Poulain,2001; ino et al.,2001). ndeed,it is becoming inappropriate to think ofbrain function solely n terms of neuron-neuron connections(Gallo & Chittajallu,2001). Neurons are only part of the story.

The importance of glial cel1sn brainfunction may be reflected n the greaterprevalence of these cells in intelligentorganisms.Many simple organismshavemore neurons than glial cells,but glialcells outnumber neu-rons in the humanbrain by about 10 o 1

(.4,


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92 Chapter NeuralConduction nd Synaptic ransmission

Two Mechanisms f Neurotransmitter eactivation

molecule tReuptake

synapse:euptake ndenzymaticegradation.

EnzymaticDegradation

tion, astrocltes have been shown to communicate withneurons and other cells hrough gap unctions (Bennett eta1.,2003). hus, he recent ocuson glial unction is reviv-ing interest in gap junctions. Clearly,gap junctions playimportant roles in human brain function. The next fewyearsshould seemajor advancesn our appreciationandunderstanding of this meansof cellular communication.

t

to establishn mammals (seeBennett,2000).They werefirst demonstratedin mammals in the 1970s,but fewmammalian examples accumulated over the ensuingyears-that is, until recently.Recent technological developments have led to thediscovery of gap junctions throughout the mammalianbrain; they seem o be an integral feature of local neuralinhibitory circuits (Galarreta& Hestrin, 2001). n addi-

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Now that you understandthe basicsof neurotransmit-ter function, let's take a closer ook at some of the neu-rotransmitter substances see Deutch & Roth, 1999).There are our classes f small-moleculeneurotransmit-ters: he amino acids, he monoamines, he solublegases,and acetylcholine.n addition, there is the one classoflarge-molecule neurotransmitter: the neuropeptides.Most neurotransmittersproduceeither excitationor in_hibition, not both; but a few produce excitation whenthey bind to someof their receptorsubtypesand inhibi-tion when they bind to others.Al l of the neurotransmit-ter classes nd individual neurotransmitters hat appearin this section in boldfacetype are outlined in Figure4.15 ater in this section.

are amino acids-the molecular build-ing blocks of proteins. The four mostwidely acknowledgedamino acid neu-rotransmitters are glutamate, aspar-tate, glycine, and gamma-aminobu-tyric acid (GABA). The first three arecommon in the proteins we consume,whereasGABA is synthesizedby a sim-ple modification of the structureof glu-tamate.Glutamate s the most prevalentexcitatory neurotransmitter in the mammalian centralnervous system;GABA is the most prevalent nhibitoryneurotransmitter.

, .1: , . . rt . i , i l t i : t , . i . t i i . ; ;' , . i : . , , i t l ;J ' i ; I l i i t l i ' ; : ; i , l l i l * i : . r ' r ' ' : ,Monoamines are another classof small-moleculeneu-rotransmitters.Each s synthesizedrom a singleaminoacid-hence the name monoamine one amine). Mono-

ON THECDTheAminoAcidSynapsesmodule umma-rizes he effectsof hree minoacidneurotrans-mitters-gluta-mate,CABA, ndglycine.

The neurotransmitters inacting, directedsynapsesn the vast majority of fast-the central neryous system

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