'Inside' Information on Synaptic Action
ur Jaqlou? lsure8B alsJado 01 JIASIT uoxE eql olq apoJpala aus B aJnpoJlur o] uoltprBdaJd stql qlr^\ elqrssod aq lqSru u leqt (aror ) a1o3 'S ypuesurnJ'f .Hols?11a,lrsz (oaer).{a1xng 'g 'y puz (salqg u113pog ot parrncro ll alerqalre^ Jo esoqt ueqt ra8.re1 saru1l d*$ a.re suo,tcas-ssorc iioq,n tpodoieqdac iql 3'o sarqg-a,,r.reu luer8 eql o] uopuaue ur,tu.rp Suraeq EunoS .7 .f 'la sJl ,tuaurSas plnorrr eTds eqt os puu txeu aql ur aslndurr qsa.r3 e ;o uorle.raua5 aql roy parrnbar tuatx? ue 01 palrcxa aqt "aJE Jo p?aqe auerquau aqt sazrrelodap dypnpe aspdu.rr alJau oqtr .eqnduu t?ql pa^roqs urlSpog u?lv 196l u1 ue 3o a5zssud aql uo a^Jsu 5rl1 JO Uorpas-ssoJc eql ]3 apoJpala puocas B o1 a r]ElaJ uorxagap a,rrle3au e poJalsr8al aprslno aql uo apoJtoala ue asnecaq uoBarl"^ a,rr1zSau aql lua^a srqt palp, pzq ,aslndurr alJau aql Jo alnl?u l?orJlcala aqtr Jo leJa^ocsrp .prrout,(ag 'o.raz -slog nO saqceoldde tuautorrr u .ro.; 1zr1ua1od auurq eql -ruaru luql os (acuepnpuoc Jo as"arcur uu) flqrqearu.rad .;o es"-aJrur alqrsJa^al uappns a sr luaJlnc pcrJpela Suzr.rrlodap e- gas ,{q dn aslnduu .ro 1zr1ua1od uorlcu aq1 leql pafelnlsoa Arorql .,{ayxn11,urr13po11 s.uarsruag ( p.re.rag'8uag,sau.(ay ) sluaurat?ts asaql qsrlqBtsa ol papaau uaaq sEq ^\aJ l?ql 1"roar luluaurlredxe Jo lunoue .(.rzurp.roe.r1xa aql ,rlar^al ol aJaq .+ualuoc alqrssodurr s.r lI runrsselod s1r f,q paurut.ralap dgarqc plnom uoxe aql ]Q Jo aplslno pu? (a,rrle8au) aprsut aqt ueal$.laq ('A[I of-) IEuua]od Surtsar er[J 'uox" aql ur runrsszlod.prng JEJnllacBJlxJ aql ur uort?riuecuoc q8rq ur luasa.rd sr unrpos 'aptrolqc pue urnrpos o1 .,(lrpqeau.rad,ro1 .(.ra^ s?q lnq urnrsselod ol alq?eurad sr auzrquau a^lau arll .(zoot) uolrerrcxa go ,{roaql s.ualsu.rag }uauotu z ro3 1pcj.r o1 .{rzssacau'.uou sr l;
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9 ralduqC 116 CHARLES sCoTT SHERRINGToN the extracellular fluid (or a corresponding artificial solution) and so procure direct evidence as to what actually happens across the nerve membrane during impulse initiation. They were rewarded by the unexpected discovery that the nerve-action potential exceeded the resting potential. On Bemstein's theory the action potential across the membrane ought to have gone, maximally, to zero corresponding to some 7o mV. Actually it swung 30 mV. beyond it to the positive side. Years of exacting work finally led Hodgkin and Huxley to a quantitative theory of the ionic events during the nerve impulse, which is now well supported experimentally. The essential components of the ionic theory are that the sudden increase of conductance elicited by the depolarizing current is a diphasic event, beginning with a transient sodium permeability and changing to a potassium permeability in the falling phase of the spike (or action potential). During the first phase, positive sodium ions from the outside flow into the axon and this process is recorded as the rising spike. In the second phase, the transient sodium conductance is replaced by the potassium conductance during which potassium ions move outward down their concen- tration gradient. The mechanisms responsible for producing and timing the exchange of the two ionic events are unknown, but the sodium conductance increases explosively when the mem- brane has been depolarized to a certain threshold value. Evidence has been presented to the effect that, when an impulse is generated in motoneurones or at the motor end-plate, this process is actually preceded by a slow depolarization. As to sense organs, the author long ago postulated that'generator potentials' would arise in t}tem as a sequence to an initial process possessing specific sensitivity to the adequate stimulus (for instance, a photochemical reaction in the retina). Such generator potentials have since been recorded in several sensory end- organs, but it would carry us far beyond Sherrington's influence on nerve physiology to review this work. Our present concem is with the intracellular recording from motoneurones. In the hands of Sir John Eccles and his colleagues, especially J. S. Coombs, D. R. Curtis, and P. Fatt, this has proved very rewarding and has clarified many of the problems raised in the previous chapters. This method was an offshoot of the 'inside' approach initiated by Hodgkin and Huxley. It pre- ( I(x)d-rr \r'l'u()]-rol\ '\: ll -rossrlo.r(l .]o ,is.!-rno.r .ig) (rxrt J,)s) r,/.brlrA.1?d' PLtr 1)tiioptlll).1 trr,rs,r.rd;-r ot rrollirrr-r-r,rr1q ,iq l).)luls 'loo(l.r)\r'l ]r: sirr()trr.roqrl srllr.\ LrosrlrrroLl.y_ rrll lo ,).rlr l.l_ .).rnl.)) l rrlt.]o IJUN l] lr() LLI)l(lllr:l I ,/11(I
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r.;IW e .ratr3e prlualod olldeudslsod ralrlap o] uaes sI rl 6t 'SIJ uI " i arlds u 1rc4a ot l?a,u ool sl luqt stueJegu .rrlncsnur 1 dno.rg eql rrro+ Icoqs e o1 puodsar auoJneuolour aql saop 'acu€lsul roJ ',troH 'xageJ orld?u-{souour aql suJacuoc 'qlrm ur5aq ot uorlsanb snorlqo aql 'a.raq dn ua{"} aq uec p.raua5 ur d8oyoxaga,r prre uorlc? cqdeuf,s qlrm pe[racuoc .(1lca:rp asoql f,po 'fzm 6II NOTJCV srJdVNl,S NO NOTTVI^IUOdNT .SOrSNr, 12O oHARLES sCoTT SHERRINGToN delay. In previous chapters the problems were defined to which we now have answers in intracellular terms. Shenington's central excitatory state, for instance, was a graded differing in this regard from the all-or-nothing -eve.nt spike. Similarly the excitatory postsJmaptic potential can be graded in magnitude by altering stimulus strength, as shown in the figure. The moment this potential reaches threshold value, which in cat motoneurones takes place around Io-15 mV., the cell fires a spike, as is illustrated in Fig. 90. Normally the motoneurone is rarely excited by synchronous
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lnsac --!^\ T-.r.rffi a msec b Fig, 90 (a) Postsynaptic response of a motoneurone has been recorded intracellularly several times on standing-\./ film. The response is near threshold and so sometimes elicits a spike action potential, sometimes not. (b) Similar record showing spike rising from slowly augmenting post- synaptic potential. The lower record is electrically diflerentiated to show rate ofchange of spike potential emphasizing the two phases (cf. Plate 1 I ). (Eccles, The Pfusiology of Nerue Celh, The Johns Hopkins University Press, Baltimore, 1957) volleys of the kind used in the experiments, the nearest approxi- mation being the brief stretch reflexes of which the knee ierk is the most familiar example, Instead there would be asyrchronous bombardment of the membrane by impulses at a very large number of slmapses and most of them would be arriving poly- slmaptically across intemuncial cells. This is easily understood when it is realized that for a total of gzS,ooo neurones in one segment (the seventh lumbar segment in the dog), the numbers of interneurones and motoneurones are related as gO to 1 (Gelfan, 1963). Several counts have been made of the average number of s)mapses on a motoneurone. A generally accepted figure is z,ooo ( Barr, Wyckoff and Young) but for the largest IEraqduad uI parpnls uaaq ,(Isnol^ald pEq lI aull-aseq aql sanp^ spr?Ir\o} Isuualod Jo Srrl^rs ? sr sqJ'Iu 'SIJ ^rols q^{olaq pal?.osnlr 'alrds aqt 5ur,ra.o11o3 uortezrrzlodrad.{q-Je}E erll sr s3urpug .rofeur :Iaqt Jo auo 'san3eallo:r stq puu selcag Jo rlJo,tl, pcrl.{1eue aql ur slool pJ?puzts s? pasn uaaq osl? aAEI{ saxagar clldeur(souotr^J '1o.r1uoc puof,aq sa nos uro{ sasindrm paf,elap dq pagrpourun eu?Jqruau auoJtreuolour pete^Ilce dlpcrldeu.r(s aql 3o sag:adord aql Iuo;qcu,{s ,{q pagru8uur pue a1e1s pagl:nd ? ur salzJlsntl 1I asnecaq '( 9 .raldtq3 ut pa.{\al^ar 'r1.rom s.p,(o11 3c) qczordde pluarur.radxa rre s? alqenl?A pa,to.rd suq ?IcSIu"
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d1rq311s 31asrr ur q5noqt'uoue,rrlce cgdeuf,souour snouo.rqcu.{g 'uop?ruurns ,(q a1e1s ,(rolelrcxa lzrtuar aql dn plnq o1 uors.radsrp produral ur Sur,rr::u sasyndurr crlduu.(s.(1od Jo .raqurnu a8rey u ,(q paurel sr euoJneuolorrr (l1,t1lcr puuou eq] -ur"rrr " Jo l?q] 'e.roJaJaq] 'aur8eurr ol s?q euo selrJpuep eqt uo lsal aqr ',{poq 1ac aqr uo aq plno.{\ pJtp-auo araur qrrq,u.;o ooo'ol aJnBS " 'sasdeu,{s Jo pa]Eurrlsa uE sa,tr8 uz;1ag 'd 99Jo ralaurerp e qlr,r^ sauo.rneuoldur lGl NotJSv cIJdvNxs No NoIIvhIuoJNI .3cIsNI, 122 oI{ARLES scoTT SIIERRINGToN nerves by Gasser and there found to be accompanied by a parallel reduction of excitability. In the motoneurone afier- hyperpolarization is far more prominent than in its axon. Since it represents an increase of the membrane potential, a repolar- ization, it is accompanied by a reduction of excitability. Taking a concrete example, assume that the membrane potential had been - 70 mV. at the outset and that the spike momentarily had reduced it to ?o+go: roo mV., after-hyperpolarization might have carried it to zE mV. at the lowest point of the sliw change illustrated in- Fig. e3. Motoneurones differ a great deai among themselves with respect to duration and amount of after-hyperpolarization, and this, as we shall see, is important for the understanding of variations in firing rate (Chapter ?), because evidently firing levels of depolarization havi to be re-established by temporal summation from the initial position at the end of the spike. Much information has been obtained by using two stimulat- ing shocks at varying intervals. In the experiment, analysed in \ig. 22, the first shock is antidromic and hence non-synaptic. It merely serves to set up a spike. The second shock ii ortho- dromic (afferent) by the monosJmaptic route. The question raised by this arrangement of the stimuli is : how soon after the discharge of an impulse is the motoneurone prepared to deliver an excitatory postsynaptic potential I It was found by Coombs, Curtis, and Eccles that the postsJmaptic potential is iiminished for several milliseconds after the antidromic spike and that at an interval of about t.g msec. it is practically non-existent. This also means that, if the orthodromic impulse is prevented from generating a s)maptic potential for I.z msec., it cannot do so at all and therefore the depolarizing activity at the syrapse itself cannot. have lasted any longer. In Fig. as (a), the piocess of activation itself is showrr by the broken line. The monosynaptic postsynaptic potential is traced by the line drawn in iull. In Fig. es (b), there is a graphic presentation of tie subsynaptic cuments generated by the activation of one syrapse. In order to depolarize the cell, the cument must be outwaidly directed across the membrane and hence the subsJmaptic current must take an inward course. The brief bursts of subs)maptic currents at a large number of sJmapses may be regarded as the elementary evenis in s5maptic cud?udstsod sll ,{q pat?rrsnlll asrnot aurq aqt s?q uorl?trcxa .Jall?I crtd?udsouou ',(eru 1r su ]?rp ofl aqt uuql ,(1,lrro1s e.rour puodsar 'auo.ntauolout eqt Jo ,{poq 11ac ,ro ?u.tos aqt uro.g pza:ds ,salupuap ]snru pa3a aql qorrlr'l. ol aql "{Iq?qord pu? sluarrno c-qdeu,{s padelap Jo urnnprsar e aq drur ararlJ .poo}sJapun ,{11n; aq or przs aq }ouu?c esrnoc aurrJ stl pu? rlWB xalduroo arour ? ( .(u sr 11n; u1 u,ne1p aq1) prlualod crldeu.{slsodiqa ) ez '!l-{ r1 ."",t ua1o.rq,(q pat?Dsr1l1 sr }prlt t)aJa aqt st sttt puu pup '.,(lrceduc acu?]srsal 'stuetsuoc l?orJtcale o,nq s1r jo pnpord
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Fig. 23 (a) The unbroken line is the mear of several postsJmaptic potentials in cat motoneurones, while the broken one showi the p€iiod of the subsytaptic currents required to generate tiis change of potential. (b) Diagram showing the subsynaptic currents during th; activation of one synapse. The synaptic cleft between the knob and the membrane of the motoneurone is magnified out of scale, The current passes inwards through the subsynaptic area and outward through the cill membrane. (Eccles, ?le Physiology of Nerue Cells, The Johru Hopkins University Press, Baltimore, 195?) ions across the cell membrane are delivered bv the terminal impulse directly or whether here, too, a chem"ical process is fulfilling the r6le of acetylcholine at the motor end-plate. The answer will be postponed until synaptic inhibition has been discussed. The further problem as to what ions are concerned in the three changes of potential so far described, the postsyraptic potential, the spike, and the after-hyperpolarization, his been studied a great deal, mainly by Eccles and his colleagues, but it 'Vu m q15ua4s SuIzll?lodaP IEJ " '('duv 6-0I:) luarrnc Jo uoucunJ ? sE dcuanba{ aslndul a.rnseaur o1 alqrssod uaql s1 }t pue 'opo4cala a,rrlz8au aprslno aqt ol au?rqrueur aq+ qSnoJt{r ssed 1y'r luarrnc 'a,rrlrsod apBtu sr apolcala aqf 3o du aql 31 '(SSor ) 1u.lg puz rrlury,(q pasrrr.ap anbruqcal e '.&elpdec-o.rc1ur aqr .yo dlr aql q3no.rql luarrno pr?,lrtno uz Surssed dq parpnts aq u?, qcrqAr. qcuo.rdde J"lnllal?Jlur aqt 3o lcadse srql ur palsa -Jatu ueaq seq (qlrurg'ssauoqs'11eu.ray'1rue.rg) .,(.ro1zroqe1 rn6 ',{cuanbary asyndrur saururra ap luaJrnc au?Jquraur p.ru^\lno
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aql qcrqar fq salm aqt Jo a8pa1,r,rour1 a.rrnbar (raldeqc lxau eql) IoJluoc rotour o1 3rn1e1al suralqord erp Jo lsoru tnq Jnorleqaq xagar .{1uo 1o1q ',(1a,rr1r1ada.r uoqcunJ sauoJnauolou aq} ,lrorl Jo uorlsanb aql sr .tnar,t Jo ]urod :no uro{ }saJalur paJrp alotu JO 'paJalsoJ uol3uu.raqg l"ql s?apr Jo tas aql rog acuecgru5ls altlll Jo sr qcrq& IJo,r\ o^rsualxa srqt ,lrarlar o1 ,{3o1orsi(qdorlcala Fcrtaroaqt otur JeJ oo1 sn ,{xec ppoa,r 961 NOIJCY CIIdVNAS NO NOIJVI,{UOdNI AOISNT 126 CHARLES scoTT sH,jRRINGToIi imitation of how an asyrchronous barrage of impulses at the terminals will depolarize the cell. The result of such an experi- ment is shown inFig. z+. It is evaluated graphically in Fig. 25, lmp /sec o
Fig. 25 Frequency of discharge plotted against cun-ent strength for tlre Dlotoneurone of Fig.94. Curve I shows a constant slope of 6.9 impulses per sec. per nA and is derived ftom the O.S sec. following the Iirst intelval; curve 2, the same after 1.3 sec. ; curve g, the same alter 2-6 sec. with the measuring time extended to 0.5 sec. The stope constant of g and B is 4.1 impulses per sec. per nA. (Granit, Kernell, and Shortess, J. p,4yszol., 1963, 169, 743) the frequency of discharge being plotteil asainst current strength. , Clearly the relation between current intensity ancl rate of fi_ring is ljnear within the range of normal frequencies of dis- charge. There is also a process of 'adaptation, implying that the loor I"LuaA E olll1 ,{llEcrurorplluE dallo^ ? pars oq,t\ ,(asp.rrg atrl aqr ,(q srot ur para^ocsrp aJe^r ^r?qsueu EIac ^rzqsuall '(t9ot 'nslaloy pue '112g 'salccg) 3df1o1o:d rraql sE uasoqc aq aJaq IIL{I ac ,,rr?qsuag pa["]-os aql pus 'IoJluoc rotorrr Jo suralqord 1p ;o Surpuels.rapun eqt JoJ lsaJalur alq?leprsuoc Jo a,re proc purds aq] ut sauoJneuJalul 'uou?Inups o1 asuodsar ur sprlualod cpdeu,(stsod alz.raua8 o1 punoJ uaaq a^Eq r{crq^lJo IIe 'sa}?rqatJa^ur snorrE^ ur sllac e^Jau lua.ragrp duuur lea.r8 e pr-re sauoJneuralur qloq ot papuelxa uaaq szr{ qceo.rddz JElnllec?Jlur eqt tnq ,sauoJneuoloru ut uopellcxe qllra pauJaouoJ uaeq ,{1uo s?q uorssncsrp aq} r"J oS 'uon"I.uxrls paurslur?ur ot pue a3ueqc Jo el?r ol qtoq puodsal o] paqclzur aJoJ .a5ruqcsrp 11a,v!. -aJeql aJe sue3.ro'pua pu? seuoJnauolotrAi 3o ,(cuanb -a{ peurelurzru Ja,lrol ? o} uorleldepz,(q u,top el}}as dll?oruol Sutpuodsa.r;o alqzdec asoqt qcrq,r\ JaU" 'uouelnurps.;o a3ueqc.;o elur ot alrtrsuas osp ueql ar" pu? sat?J q8rq te Surrg uels uec suu8ro asuas lsotrAJ'rouu"rx srqi. ur ale.rado sde,,'r,p p,n qs;rnq Frtrur Jo 8ur;g aqt ol patcrJlsar are rlcrq,l\ sauorneuolou asoqtr pue 'lndu aql Jo JaSIIdurB luarcga {ta,r e sr auornauotour aqt 'q3rq sr ql8ua.os tuaflnc ol Surrg 3o a1z"r 3ur1r1ar saarnc aql go .auoJneu adols aql uaqal ',(lpprul 'stl] Jo alns?eur ru sr adols aqa -olorx aql Jo ..rolreJ uolt?cglldure, aq] Surugep 1e s1dura11u se pap.rz8ar aq osp ,(eru peqrlJsap 1sn[ slueur.radxa aqa 'uorlelnruqs ft InflaceJlur paurulureu Sur,rnp sa,r.ordurr dlunper3 .(lzrtrur qrrq^\ uorlezrr?yodred.(q-.ra13e,(q pa,{e1d osle .3rg sr Sur:g cruol ur a1o: luelrodrur uz xql s,/rorls 97 3o sp:oca.r arll Jo uortrcadsur asolo pu? 'a3:eqcsrp;o al?J eql uo tcaga 8ur -zrlrq?ls ? s axa auoJnauolour aql Jo aueJquau aql luql saqdurr .ssaco,rd aarldupz, aqa 'sasuodsa.r crszqd ul u?d a{e1 ,{luo plnoc 'pulrou aq 01 paurnss? JI 'ad,(1 srqr .;o sauolneuotou ]?q1 1sz3 os uorleldzpe pue q8rq sl tuelsuoo adoys aql tnq teaurT osl" sr .{lrsuatut luarrne puB .{cuanbar3 ar ds uaa,,rrlaq uoll?lal eql sasec qcns u1 'qlSua.rts tuaJrnc aqt Jala]?q,lr 'uor}"lnuqs aprsur .vu 01 lsJnq JarJq ? u?ql aJour ars ol asnJal sauoJnau auos .rad cas .rad saqndurr 9.6 punoJu e:e sluptsuoc edols ,pa1depu, 'aurl 3uo1 e:oy Sur5reqcsrp rde{ aq u?c qorq.la,.sauornau -o1oru Sutrg.(ypcruol uI 'lu?tsuor adoys ralleurs e dq pazr -Jalc"ffqo anIE^ .pa1depu, .ro .{pears z sa.nnbce os :o puoaas " JIEri ulqrl,lr pu? uolt?lntulls Jo lasuo aqt 1e daals s1 arr..rnc aqt ;o adols LAI NOIJCV CIJdVN,\S NO NOIJV}'(UOJNT .S(ISNI, I98 CHARLES scoTT SHERRINGToN while fine electrodes had been thrust into the spinal cord in the neighbourhood of the motoneurones for recording. He then found cells which fired to a single shock in the marrrer illustrated in Fig. eo (b). The initial frequency is extremely high, t,ooo to l,5oo impulses per second for the first pair of spikes, the rate of firing then petering out in the manner illustrated. The dis- charge followed after a brief latent period and its changing rate of discharge was imitated by a depression of monosyraptic reflex excitability which started rapidly and slowly diminished. The reflex excitability was studied by monosynaptic testing ( Chapter 5), for which one portion of a ventral root was used while the rest of the root served for antidromic stimulation. When the Canberra group retumed to this problem they were able to demonstrate that, coresponding to the discharge of the Renshaw cells, the motoneurones became repolarized for some forty milliseconds along a curve whose depth, just like the mono- slnaptic depression, reproduced the time course of rate of firing in the Renshaw cells. This curve, together with the circuit diagram (Fig. zo (c) ) that was suggested by the results, is shown in Fig. 26 (a). The axons of the motoneurones were actually found by Golgi to possess branches, called recurrent collaterals, which return to the grey matter of the spinal cord. In the diagram these have sJmapses on the Renshaw cells which in their turn repolarize the motoneurones. This detour gives the circuit its latent period. The ensuing repolarization will aug- ment after-hyperpolarization but while the latter is in sequenie to the spike, and thefefore restricted to the firing cell, recurrent repolarization is caused by synapses which the Renshaw cells establish by their terminals converging upon a large number of motoneurones (Szentigothai, re56). By definition, the effect is therefore an inhibition. Antidromic or recurrent inhibition at the cell membrane thus appears as a posts)maptic potential of opposite sign relative to its excitatory counterpart. Actually, this was not the first example of a posts1naptic inhibition thit Eccles and his co-workers encountered, but it is a particularly lucid case because here we possess both the circuit diagram ai well as the firing of the internuncial cells. How definite is the evidence for the sJmaptic nature of anti- dromic inhibition ? Could it not be a depression exerted by currents spreading from adjacent motoneurones activated anti- b9 'st 's961 'lrs ['lslltr'nqa{oy pue't}ed'sapcg) sauolnauololu oq} uo sasdEu,{s ,{Jolrqrqul a^eq .ranpl arIJ (I) sflar ot unr qcrq,u slEJal?lloc luArrncer puB suoxB llaql wl,\,r (lI) ^reqsuausouornauotoru Sur,ltoqs rue,rBulp lln rC (.) Aur 9.0'apcs lzgualod : casur u1 arula ,{le,rqcadsar salcsnru ;o dno:8 pauo.rad daap aq] pue 'unJo!131p m8uq .ora{ 'snlwauro4soS ol suoxe Joloru oql q s.{aIIoA .JluoJppue .{q pa1p11a auoJnauJalur aures aqt Jo sasuodsal o:e 'pJE,$u.!lop 3ulo5 'sprocal Jaqlor 'suoxP Jolour snsourpualuras-sdeclq eqr u1 (a11o,r cruoJp!1ue ue fq auomau.ralul ue u1 dn tas asuodsar clurq qr eqr s.{4orls pJocar raddn aq1 (q) 'r1ur 9 'apcs 1eltu?lod :'casru ul erurJ asrou ruopu?J alEupulla o1 sace.rl 1up; ftro.1 lnoqp Jo uolllsodrurradns aqt ,{q apeur a;e spJocal IIV ppualod-:a13e a,r111sod aql dq uolleclduoc ou s1 araql procer Ssouuaddn aq1 u! os 'uoxe Jotoru u,,1 o s1r ur eqndug aql dq fflecluroJprlu" pap?Aur lou se,\\ ouoJnau -olour aqJ .f,aIIoA cruroJpltu? srreltreld e Jo lcaJa o.raz s,{ oqs pJocar lsa^{ol aq} alq^\'suoxe rolou snsoupJqluaururos oq} ul puE snsourpua} -luas-sdaclq aql ul sfallo^ cruo.rp!]ue f,q pacnpo.rd suopezllelodradf,q 'uoDoq ot dol uro4 SulpEaJ'^\oqs sa^Jnc ureur aqJ sprocal .reFllacE4ur o,ltt }srg aql aloq? u,{\oqs s; p,roc pulds arp Jo lcadse luatul-osJop aq} uo p€al a.€JJns E ,(q popJocal ,{lsnoauelpurrs pqua3od aqJ 'euolnauotoru snsourpualluas-sdacrq e ruo4 SurpJoJaJ .relnfiacp4q (e) 96 .8tg 19O cHARLES sCoTT SHERRINGToN dromically I Such arguments which had to be considered when Renshaw published his observations need not be taken too seriously today. At the time, depression of motoneurone excita- bility to antidlomic stimulation of ventral roots was not unknown. It had been seen by Denny-Brown in 1geg, and. Eccles and Sherrington in the early thirties had employed anti- dromic stimulation of motoneurones in experiments rvhich it would serve no purpose to review in this connection. Even recurrent collaterals had received some attention (Graham Brown, 1914,, Forbes, t9s3) but the time was not ripe for the handling of such problems. What really became decisive for the new developments was the discovery of the discharge from tle Renshaw cells coupled with intracellular recording from adjacent motoneurones. Eccles, Fatt, and Koketsu could then prove that the amount and duration of the repolarization of the motoneurone depended upon the strength of the antidromic shock in the same manner as did the frequency and duration of the disbharge of the Renshaw cells. The latent periods of the two eyents also agreed with this interpretation of cause and effect. Furthermore, the dis- charge of the Renshaw cells and the inhibitory postsynaptic potential were both augmented and prolonged by eserine which neutralizes the esterase that normally removes acetylcholine. Remembering that the motoneurone acts by liberating acetyl- choline at motor end-plates in the periphery, it seems reasonable (on Dale's principle ) that the recurrent branches of the same axon also would be cholinergic and hence liberate acetylcholine at their s1mapses on the Renshaw cells. Other experiments with drugs also show the same close parallelism between moto- neurone excitability and recurrent inhibition, and differentiate it from electrotonic effects recordable in the ventral roots (V. J. Wilson). Eccles and his co-workers have also succeeded in obtaining some intracellular records from Renshaw cells which proved them to be depolarized by antidromic stimulation. This is the sj'napse that was found to be cholinergic. The nature of the postulated transmitter at the second syrapse, the one established by axons from Renshaw cells on motoneurones and which causes the inhibitory postsynaptic potential, is unknown. In vertebrates, while the number of candidates for the r6le of transmitter sub- uo sFurural frorlqlqul aAEq plno.,rr auornauotoru Jo punl auo uo sleurruJal d.roletrcxa suq qcrq,r erqg tuaJage aql l?ql f,Ia{rlun .raqler pa.readde oE? lr arrrp aqt tV '(Sreqpun1 osle 'p) a1not ua asdeuf,s leuorgrppp u? pJqsllq?tsJ aAEq sJe{ro^\-oJ stl pue sJlJog uosear slql ro3 pue asdeu,,(s auo o1 SurpuodsarJoc aurl aql .( ,(q pa,{e1ap Suraq ur.ra11uy eqt uro{ sragrp U uorlzzr:elodap ) prlualod cgdeu,{s1sod ,{rolelrcxa aq} qtt,lr pa.reduroc (uor1 -zzuulodar) u8rs alrsoddo;o 1nq pgualod crldzu,{s1sod papur8 e osle sr ssaco;d srq L'La '3r1ur ua,rr3 sr uorlrqrqur slqt Jo eJnlcrd .ged ftlnllac"rtur aqJ 6r pue l, t s8l.il ur aloq? paluesa.rd -ralunoc .{rolelrcxa s1r o1 purllpz anr] u snq] pue cqdeu.{souout sI 'oot 'tr leq] asuas eql u! palrp sr tr l?ql surBtur?ur rts puz
(sae 'ost 'sgat 'ptsfitd '! '$et pue'salccg'squooC) uopezJftlodredfq aue.rqruaur Suqeclpur suoFauap pJet\u.rop rspJocal JElnllaa"ilur JoJ .Aur 9 s^\oqs alEcs a8etlo^ 3qJ 'sac?Jt tulEJ f,uoJ lnoqe.;o uorlrsod.rodns aql f,q peur,ro.y al" splof,aj IIV '(a) ol (p) tuo4 pue '(c) ol (q) tuo4 '(q) ol (e) ruo4 :tellualod cqdeu,{s .(&l^g€gau -lsod .{.rol-rqrqur oql Jo azrs eql u! suoqeper5 aarqt aq} atoN SurTleu5rs suogcagap p:er'ru,rop) aporcala ocpJrns E,{q }ooJ IEsJop SrI aq} tuo4 papro.al are qcrqt\ spJocar Jaddn eql trq u,roqs sr sE .azrs Sursea.rcur ,{1enssa,r3o.rd .1o ,{a11o,,i sdecr.rpenb e o} auornauolou snsourpua}luas -sdaclq v 3o sasuodsar rqn acuJlq ?ql a^€ sp.rooal Ja,{o.I /A '3r.4
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.(s uoplqlqq tcarrp lr pall?c pEq pdol.I p* s s.raldeq3 3c) slsr -uog?lu? Jreql Jo sauoJnauoloru eq) uo axa sluarage .(rolzlrcxa crtduuf,sououl qsrq^\ uo4rqrqur pco"rdrcar eql Sursn salJrg puu 'squooC 'rlcorg ,(q z96r q paqlt3sop lslg s?,y\ 'sl"ratul -Ioc luarJnsal qtr^{ peurBlqo s}lnsal Jo srseq aql uo ararl pacnp -org uaaq s?q qrlq^\ 'lellualod crldeu.(s1sod .(.rolrqrqur aqa 'aJnlpu puuetsqns alorrr acueprle fq " Jo palroddns sr uoqergrtuapr qcrq,{t ur as"c lseq aq} 111ls sl ns}a{oy pu8 '11?-{ 'salsca {q EIec /lAErlsuau aq} }? uol}Btlcxe el8raurloqc laseaJcur Jo SuIpuS aqt o1 spua] sasd?uds lelluao 1e sacu?ts I6I NOITCY JIJ,dVNAS NO NOII,V}IiUOJNI .gCISNI, 139 CHARLES sCoTT SHERRINGToN another. As pointed out in the previous chapter, this argument seemed sensible if one could assume that slmaptic specificity resides in the terminals. Recently, however, Tauc (1952) has obtained evidence with the mollusc A!$nia which places speci- ficity on the subsynaptic side of the membrane. In his prepara- tion the nerve cells are visible and so can be punctured under the microscope while micropipettes can be used for direct application of acetylcholine. Some cells responded to acetylcholine with postslnaptic excitation, others with postsynaptic inhibition and in the two types corresponding effects were obtained by afferent stimulation. Since rve have good reasons for concluding with Eccles that different ionic mechanisms operate in excitation and inhibition, it is of considerable theoretical interest to possess a preparation in which the chemical transmitter substance appears to be the same for both effects. It is hardly necessary to supplement the evidence with further experiments from the work of the Canberra school and other research groups studying mono- and polysynaptic circuits in different cells and animals; it has been proved beyond doubt that excitation and inhibition are represented by postsynaptic poten- tials of opposite sign. The pyramidal cells (Phillips, rsso) might be added in order to include the brain, and the crustacean stretch receptor (Kufier and Eyzaguirre, to55) would be a good representative ofa sense organ provided with an inhibitory terminal from a centrifugal nerve, In the latter, too, excitation is a depolarization and inhibition a repolarization of the cell membrane, and both events can be studied in a cell that is visible under the microscope. After the discovery of the postsynaptic inhibitory potential the case for chemical transmission seemed very convincing. If one were to assume that the electrical impulse in the terminal would cross the subsynaptic cleft and the cellular membrane to produce the necessary subs;maptic current, how then could the same current from an otherwise identical impulse run in an opposite direction, as it would have to do in order to produce the inhibitory subs;maptic current I The chemical mediator seems, in fact, unavoidable in a system of the type which is so common in vertebrates, i.e. a small surface, like that of the snapse, faced with the task of exciting a disproportionately- laiger structure (cf. the motor end-plate, Chapter d). Admiltedly it OI -nururp Jo uoq?luaul3n? duP lsoull? uBaIIr 01 asuas pJeuas aJoul 14 pasn osIE aJ" .uoBlqlqu, puE .uol]"].Irxa, srrJal aqJ " 'palldd? aq seurllauros rI?3 saPoIcalaoJOII[ crldEu,(slsod puE -aJd qloq uaql 'adoosolclu aql Japun pa'^Jasqo aq uuc uouerzda:d aqr leqr a3elue,tpu 1ea'13 aql qlr'tr Jalueu apr,to:d ua1.;o s[ac alzrqaua^ul slqr uI (ol -r:adxa aql ^pla5 paJJaJaJ 'cn"J .{q 1:o,n Jal?I aql ptrE 'eJE^\t;EH puE lcoIng) sal?Jqaua^ul tII pal?4suourap uJaq sPtl uolssltusu"Jl I?clu€tlJ 'saldriurrd.reluns 3urz111n3o alqzdec aq f,zu (uuuar aql u1 5 a) sale.rqa}Ja^ ul u.|Aomi aJE qclq^l sesdEu^s cluoxB-oxE puB (Ja]lod puu ueqdsrng ) sat"lqaua^ul q punoJ ueaq J^"q ulstu?qcaur asoq,{\ sJsdEt],\s IpJrJlJa[a .(1a.rnd e uo PasEq sI uolssltxsueJl Surzuelodap garrq pue ,(.ra,'i e u;o:3 pltlo^\ 1ui:.rnc IlPuIs ^\olloJ sasFdt[I;o lsrnq snoro8r,'r. z 'a3rz1 f,:aa ala,v' slu?tsuoc adols :.rrornr*a1ut aslndutr put ql5ua'rls ,r"qr 31 .,(uz ro; dcuanba;; luaJJn) eu"Jqureusuur uaa.{uaq dtqsuotlzla: eq} Sululaouof, uou?urroJur aplli lnq al?q a.\\ ,(1a1zun1ro;un auoJnauolotr aql ul u?q] JIru" lsnOIS qCnu ? ale,{\ acuulsqns Jalllllsu?Jl s? al?r{aq 1"i -rq, aq1 3o acuereadd?slP pue uollctlpord aqr JI (adfi"iord .rno .8uraq 11a] ,\\"tlsuau aql) sauo'rtrarualur aql leqt tno patulod uaaq dpearp suq lI salaqalral, eql Jo uals \s ,no-",, jrrl,r", aql ur Surlstxa uotlnztuu5ro crldeu'{s 3o lapout alqrssod diuo aql se pap.rz8a.r aq ,(lt.russacau lou paeu sasdeuls slr qlr^l auoJneuolou aql lEq] alaq peJaqulauai eq plnous 1, ..iyrqunn"p scrsdqdorq olur ruJ oo] sn ,{.r.rcc plno'tr stql lnq aq] pue uoll?lrcxJ;o :aurroqclfrace.Io-"ql uorrcn 3o apour '{So1ors'(qd -o.liirti qroq 8urf,;uu1c sacuelp" lenldacuoc luelrodurt o1 pa1 seq zlsy p.rEuJaB Jo spu"q aqt ut,{pnls asoq,u 'a1e1d-pua 'rolout eql ol f,llurcadsa 'saln]onJJs Jaqlo o) palonap uJJq €APt{ ol tq8no aJeds q.lnu ',{3o1ors,{qd anleu uo oJuJllUuI s.uolbulJJJqs Srrrcer ol pe;lull lou i:a.* looq slql Jo euaql aqr 31 'qcoda .roiSrrrr"qg aqr ;o+ pallJequl seuolneuolot[ lnoqe a8pal'uouq punor8{cuq Jo tunotu" alq?raplsuo, ? sI aJaq} esn"caq puE aq] ueaq azrs sll Jo esneceq sr slrlJ 'elIrnoAEJ peqsllq"lsa-lla^\ s?q auolnsuoloul aql sel?Jqa a^ uo {Jo,\l -IElnlIaCE4UI aql uI 'Sur5e.rnocua sruaas auruqc,(.t1s .,(q pazruoBeluz ale uJUo slsllualod .('rolrqrqut crldeudslsod reqr (salccg pue f,a1pe.rg ) rf,eJ JtlI lsrxe lou op srolelpau qcns t"q] u?aur lou paau srql 1nq 'sJlPJqeua^ ut sasdEll,\s l"JluaD l3 sacrrBlsqns lollltususJt I"cluaqc lf,alap o1 llncurp uaaq s?rl s6l NoIJCY SIJ,dYN.lS NO NOIrYr',{uo.{NI .scIsNI, 134 CHARLES scoTT SHERRINGToN tion of excitability in a centre. Examples will be given below. For the time being it suffices to state in conclusionlhat the two postsynaptic mechanisms are common throughout the whole animal kingdom. In his intracellular work on the postsynaptic excitatory and inhibitory potentials in the spinal cord Eccles may be said to have run out the course that Sherrington set, besides adding many new and significant observations to those briefly re- viewed. The concepts of Sherrington (Chapter s) have now been verified and reformulated in terms which for postsyrraptic excitation and inhibition agree almost word for word with those of the old Master's, as was pointed out by Sir John Eccles himself in a review of Deztelolment oJ Ideas on the Slnapse (tgbg). Postsynaptic inhibition is a stabilization of the potential of the cell membrane; it can be neutralized by postsynaptic excitation, the two processes being represented by poientlal chanqes of opposite direction; both events can be subliminal from thJpoint of view of the firing mechanism and both are capable of being nicely graded; specific sensitivity to either of the two is likelv to be localized in the cellular membrane rather than at the terminals themselves, etc. One is tempted here to quote Lord Adrian,s remark about his own work a second time: 'Reading some ofthe early papers of that time one cannot help remembiring what a pleasure it was to find that most of the inferences had been correct.'Thus it seems that biological imagination counts for something when critically applied. As a lighthouse in the dark it goes on beckoning the sailor to stay on the right course. Sherrington's early studies of reflex excitation and inhibition interacting on the same neurone had finally led him to the darinq statemenithat 'the net change which resuits there when the tw8 areas are stimulated concurrently is an algebraical sum of the' pha and ninus effects producible separately by stimulating singly th.e- two antagonistic nerves' (rsos). Wouid it rea yle p6i sible, using natural stimuli, to carry out a physiologicil experi_ ment on pitting inhibition against excitation in suih a manner that the resulr would be quantitative enough for investisatins this proposition I In my presentation of all t"hese probtemiit hai been necessary to simplify the jssue a little. Actuallv Eccles and otlrers have shown that the amount of inhibirorv rost_ sJmaptic potential depends on the level of membrane pltential 'puocas rad saslndul 9.9 uoltlq-rqu! dq a1r.r 8rn:g 3o uoqcnpel a3u;alz aql pu?*oo.I o] asolc Ilpalcedxoun-966.o eq 01 pa^oJd luulsuoc dltpuorl:odo.rd aql ..,(Il?crlsllsls paleaJt pue pa8z.la.re ate.r\ sllao BI qt.rr suolle^rasqo olt aqr uer{71\ '69.1 o1 lenba tuetsuoc dllleuollrodo.rd e s?q .ool ,11 acuaq puE lunoruB lu?lsuoc 8.,{q sprz.uu.,,r.op paurqs punoJ sr sanl€A palJasqo aqr q8no;qt alrnc eqt uaqt ,parldd" sr uortiqlqur lual -rncar Luptsuoc uaq1yoo. t eq plno.lr luelsuoc dlqeuoryodo:d e_ql lzqt SuruEJur 'ogt Jo aJSu? uz 1e ur3uo aq1 q3no:ql os '5rd ur u.u"rp aurl aqt aq p1no,t 1o1d aql puu lecrluapr aq s.,{e.u1u plnoar sarcuanba.r; o,trl aql uortrqrqur ou ala.{l aJarp JI .a}?urpro aqt uo (I3.) uorlrqrqu ,(q paurzlqo enlp^ aqt pu? essrcsqp aql tto auoJnouolour aW Jo (?) satu.r 8ur.rg snorlpn aqt luasardar oJ tuarua^uoo sr 1r sluarur.radxa qrns Jo strlnsar aqr 3urr1o1d u1 'ado1s s1r 3uua1p 1noqlra.r, .31.{ lrmou? lrrzlsuoc ? dq sp.rl,trr,r.rop 8z Jo aArn, aql UIqs lsnur uorlezr:elodar tuptsuoc e l"qt lce; eql utor; ,(ldurrs s.r{oiloJ srql 'saslndurr .sarqu 3o Jaqunu eur"s aqt aloruer s.{e,,,r1e ppoqs 1oo.r p;1ua,r luaculpz 30 uor]zlnturls cruorpgue a,trlrlada: ,(q pacnpo.rd 'uoqrqrqu tuaJJncal tuelsuor E .{roaql aql uo uaql .sarcuanb -a{ luaraJrp 1e pa.rg Suraq sr auoJnauoJol[ E .92 .Sld ul ,.dn JI auo aql a{rl allnt z Suruun.r, sr uort?trcxa qorq^t Suop a,unc aures_aql uo ,rr \op Suruunr, ueeut 11ta.r uorllqrqu lua.r.rnca: , q .JeDEI a1r.r Surrg 3o uoltcnpar V ar{} Jo aJnseeur E su pasn aq uec os puu Luarnc Surzr.relodap sq1 {1rsua1ur aql o1 .9a ;o luuorpodo.rd dpcarrp sr alzr Sur.rg leql puu tz 'sSI-{ ur a.toqz-pa1u.4s -uourap 'lcBJ aqr 3o a8palarou4 sesoddnsa.rd luaurradxa aqa aqr Bud.rur, (q salu: luarasrp ,, sauoJnJuoloru Jruol uo uortrqlrlur ",iTliilJJ'::'{"r"fi'ff,[1itueJJnJaJ pa.{oldura (unluag puz rluuJC) prqlJrsrp aq o] tuaulrrdxa aq1 .(a,roqe aas) uoll -ezr.relodar crldeu.(s1sod aq ol u,\.or{s uaaq p?q uollrqqu sql ,lruerg" pue (5a15 pue 'aocsed ) spulue a]EJqelocap ur sauoJnau -oloru Sur8.reqcsrp .(1ucruo1 uo uorlrqlqq poo8 pue .rzln8ar a,rt8 o1 punoS uaaq p?q lrncrr, truaJrnceJ iql rnq a.rz.r ,(rei osle ar? selJau .{.rot1q1qu1 arnd aoroqc lsaq aql sz Jlasrl patsa$sns a-Jo-JeJeqt uor1e.rcda.rd a]Brqalacap aqJ .sleurrue pazrleqlsazue .slerluSlod ,(1daap .yo as?c aqt ul acu?lsur roJ aue.rqurau q3rq al?q uos?al auos JoJ qcrqrl sauoJnauoloru qlr,tr Suo:aa, oB ,{uru .q31q trqaSle aqt os pue sr raltel aql 3r Srnqtou o] lxau Sulaq 9gl NoIJC\/ Crl,dyNis No NoII\I IUO.INt ,3CISNt, t36 CHARLES SCOTT SHERRINGTON In the same type of experiment and using as indicator the steady state of tonic firing of a motoneurone in the decerebrate
Fl8.,gB Results plotted from experiments on the decerebrate cat irr which.a slngle extensor motoneurine is fired ,lr,r.r,i."ii" ,i'aii"*", .F; (abscissae), whit" tr.," aimtn,iiln'oiiiel"?;";;:;;:;. ounng:t*:g"-t:lihl recurrent inhibirion. main,ained ar rares above plotted oO D;;:;..;. as.Fj (ordinates). Tie Iine above rhat d.u*n ;;;;r;; ,il";;; values passes rhrorgh the origin ,;t";;;;;;:,';";il';j;;'[:: case there would be no recurrenf ',irhinhibition that f f":Fil. ilh."rfi l"';"1"a during recurrent inhibition the drop i, ti""""rrli d'i, ffi.#;: of th^e rate of discharge o[ moroneuronq ff" p.opo.iil,n"uii;"i is I.07, the 4. J.*;;;, smndard error is o. t se r1nprl."i p". ,i". iliii.1li J. Physiol.. 1961, 168, 461) id*.""ri'jrir preparation, it seemed also worth while to investigate the effect of varying the frequency of the antidromic tetr"r: 7A;;;;;;- Ing pomts ot view ro be taken up in the next chapter,.in-i. li',jr" same time means inquiring ;,i. tn" f..p".,i:;'';i;";j,:,r: tEql Jnoco i(eur sassacord ,(uzur 'ura1s,{s sno^lau IEJluac aq} sE qf,ns eJnlcnJts xaldutoc e ul luqt ]aslno aq] 1" JealJ sluJJs tl pue 'urJal e se ,(1asoo1 Jeqt?J pasn uaaq s?q rzlncqrtd ur .uourqlqul 3o lq8noqr 1ou peq uolSuu.raqs l?qr uoElqlqq pue uorl.?llcxe IEJluac Jo slcadsu auros Japlsuoc o1 ,(lsssacau ,uou st t! uourqlqu pu? uolt?llcxa Jo uo.I]?uturns iecrzrqaSlu uo drnluac srqt;o Suruur8aq aql uroq seap-I Jo uou"cullel I?uU sqr JagV 'uaql Jo uolwuru?xa uE a{?tu o1 alqrssod uaaq seq tr areq^\ Ie^al lsaq8rq eql ol dn pa.t.rasa.rd uaaq a,rzq 'suorlunba :eaur1 aldurrs pue alzr aS.reqcsrp uo pas?q 'sursl -uEqcau \cBqpaal Wql s,{\otls snq} $o.^a s,aqlu?H qry't uosl.rzd -rrroo JnO 'sarcads u.uou4 3o ]uaroue tsoru eql Jo euo q srynat!.I urop8url Iururu" eqt uI '.tseJluoc rolour, acnpo.rd aJoJaJeql lL{\ uourqrqq }uaJ.rncag 'satzJ Jalsg te Surrg asoql ,{q lcaqc u1 plarl aq IIr^r sauornau a3u.g pale,rrlcz ,(1qaa; aqt 'sauoJnauotour 'srrloluoc ;o Surrg ctuol qlr.{\ '.,{gegurrg acu?qua snp 11r^\ uorlrqrqur IEJaI?T'eler lsBJ ? w Surrg s.rnoqq8rau paleurunll -llarr rlaql ,{q passa.rddns ara.n .(}r..'ucz raql ssalun qlac Sur.rg f,1no1s .(q pacnpo.rda.r aq plno.r asaql 'parrnlq aq s.{z.trp ppo.nt a8eur pnsr,r e go sa8pa aqt suospal pcrs.(qd .ro.; lzrp tno lurod o] araq acgns ll la.I 'ls"4uoc lensr^ Jo srs.(pue a,rrlelquenb sno;o8rr e acnpo.rd o1 'uorlurzdard papr srql qlr^\ 'alqp ueaq oslp al?q daqr pue'srnoluoc aql Surzrseqdura JoJ ursrueqcaru e sr a,{a sryruurl arll u1 uourqqm p.ra1r1 (1ua.unca.r) teql u^loqs aABq atnlEsul ralleJe{3ou aql t? slp?u pu? aurnEH '11ac Suurqlqur aqr go Surrg .teg?l Jo aluJ aqt o1 puorl.rodord sr lcaga .{rolrqlqur sy{t pu? aql 3o ele: a8;eqcsrp eql ra^alerl r '.rnoqq8rau Sur.rg e ruo.r; saslndur raqunu paxg alotual uorlrqrqur p.ralul ,(q e1"r Jo " II.r\ ]u?lsuoc 1z Sulrg gac y 'uorleurunIlr Jo la,ray .,(q las sz 8ur.rg 3o ",(cuanbs:.; Jo suJat uI palpnts uollc?Jatur puu ,(1a1e.redas pat?urtllnu aq u?c slla, pnsr^ luacefpe ay8urg'a.(a aql aaral .,{aql se raqtouu auo o] sarqu ]uaJJncal .Io .lu Jelel qcledsrp o1 punoJ uaaq e^€q sllac Iensr^ aqJ 'auoJnaurelur rru eAIoAur 01 uaas lou saop uorle.rud -a.rd s.aurp.rz11 ul paJa luaJJnre J aq;.snlnat-I q?Jc aoqsasJoq aql 3o eda aql uI (aulpr?H 'y 'g) uourqrqur I"ra]"1 pall?o-os JoJ prT?A salnr Jo e aq ot lno pauJnl paqsrlq?]sa aJe,u l"q1 "cqdar salnr o^r1 aq] asn?caq lsaralur lzrcadsa Jo a.re stlnseJ aserLl ',(cuanba;; snlnurts cnxolpque o1 puorgodord se,u uoplqqu! luarrncar Jo paga aql l?ql punoJ se.u 11 (.4crqpaa; rgI Norro.', 'rraro".r," No NoIJvI^{uo.rNI sorsNr IS8 oHARLES scoTT SHERRINGToN would lead to a reduction or increase of excitability. A tendency in the present age of micro-a:ralysis has been to go for t}te causes where previously one had to be satisfied with the effects. Most important in this connection is the so-called post- activation potentiation (post-tetanic potentiation), known for a very long time from work on the motor end-plate. As a slmaptic phenomenon it aroused fresh interest when Bronk and Lirrabee in t94,7 presented a careful analysis of it in the synaptic pro- jections to a sympathetic ganglion cell. They showed that after some seconds of high-frequency stimulation of the nerves to such a- ganglion, it became more responsive to a test shock given to the same fibres. There was never a rise of excitability to testing with any other fibres'than those actually tetanized, The effect was therefore a kind of local 'memory' in the terminals or sJmapses of the fibres that had been stimulated. It might last up to five minutes. Fundamentally sirnilar experiments were then carried out by Lloyd with the monosl.naptic circuit for the motoneurones and he also obtained the same results. Post-activation potentiation is now generally recognized as a mechanism in its own right. Partly, or perhaps even chiefly, it depends upon the fact ahat tetanized nerve terminals develop long-lasting hyperpolariza- tions. Consequently the test impulse, travelling through this region, will undergo an equivalent increase in size and io be a more elncient stimulus for the mechanism at the s5mapse. This explanation was originally given by Lloyd and has found general acceptance. To this should be added that the Canberra group ilo lraff evidence for the destruction and re-s;mthesis oT the chdmical transmitter. also being influenced by long-lasting tetani. The postactivation potentiation of this type is oi shorter duration. The preslrraptic component of post-activation potentiation ( hyperpolarization ) is of interest for several reasons. Firstly, it brings the afferent terminals into the picture, secondly, it iug- gests a method of labelling certain terminals and has been used for this purpose (Granit, Lundberg), finally, it is great\ enhanced by high stimulus frequencies suc[ as havJ been recorded in sensory end-organs and interneurones. It has, for instance, been shown to operate under physiological circum- stances, e.g. after pull on muscles (Granit, 1956) whose stretch ql.r.n parpnls ,(lluarcgns uaaq ]ad lou sEq uolllq.Iqur crldzu,{s --a.rd a:urs.(1.ru1ncrr.red'areq slq] ssncslp ol .re3 oo1 lapear 5tp duuc p1no,u 1i 1nq 'uuaurouaqd lucl3olols(qdo{cala Jo raqurnu s 5o Surpuels.repun aqt ol anlc u s1sa33ns uorgezytlodap luurur.rat l?ql u/r\or{s a.nuq .{aqa 'uorlzrtualod uor}e.tpcz-lsod o1 luupuad '.uortrqrqur crldzu.(sa.rd, Jo f,talru,n srql Jo sarpnls alrsuelxa "uI sra{.ro.!r-oo sn{ puu salmg,(q pasn uaaq acurs suq anbruqcal srq puz 'lq8raq arlds ;o uortnururrp o1 Surpual uoltuzyelodap tua,lrrapun ,taqr teqr paraloosrp (asor ) 11216 {culed 'sluerag" urls Jo slpurrure] aqt Suoure ut Icnts sapoJpalaoJclur qlrl\ '(11esr:og puu S.raqpun1) auprquaur [e] aqr Jo uorlz.rlauad o] acuanbas e su lcr3aye ue se rncco ,(psea uec uoqezrrzlodep allssacxa asnecaq aluelrodul auros 3o 1u1od u 'Surp.rocar J"Inllac"Jlxa qll,l{ petou uaeq osIE suq uou"Ar}ceur sprure:f,d pdurucoddrq eqt ur pue qlac aluqrn6 r"Ilaqarac uI'(996I'a;.un8ez.(g pue :agny) .roldaca.r qclarls ueac -?lsnro aql Suraq aldutuxa 3un1u1s e 'slla) a]?Jqaualur p.ralas ,Iepu?y ur punoJ uaaq osIE s?q uorlzlrloeul '(zsot pue racuadg ) anbruqcal r?Inlac?Jtur aql ,(q parpnts f,puara.r terlualod au?rquaur Jo uortreJolser pu? uorlBluozur 'uope,rpce yo sporred Jo tsrsuoo qcrq,u sa^er"r ?taql pepoos 'rnoys acnpord o] uosrun ur pe dlpuuou qcrq,tr (osot 'uaarC pu" ralng uol 'C) sauo.rnau pdurecoddrq a8;ul aql ur arnlual reln8ar z se puno.; uaaq dlpnpe seq pue srualsds auos m .uorllqlqur, e^Jas plnoo uolw^ltrzul '(ssor 'sd1y1q6 pue lruetg Jo sprorar relnllar?l1ur pue -e4xa) uorlez -Frlodap a,r.rssacxa Jo uorlca.rrp aql ul s8rfi,ras auzJqurau IIac aql a1tq,t Sur.readdusrp ,(11pug prr" rallerxs Sur,v'or8 sa4rds 3o 1s.rnq E ralrTap ,(pappns .{zru qrlqlr s11ac alurryn6 ]Bllaqarac aql u.r Jnsco ol punoJ s?,,\a lI 'sloJluoc Jo crJqB lleql ur rusru?qcau srql pale.rod:octn aAEq sauztqualu I?urutat pue ,(poq lac qloq leql .uorluzr.relodap sat?crpur {ro^\ luacag i(q palzgtn sr 1zql ssaco.rd a,trlzraua8 eql Jo .uoq?^ltceur, o] sp?al pue ar11 ur pue rqS1aq ,,(a1xng aqrds .;o uollnururrp sacnpo:d 1l a.raqz'r (rasneequaluu.rg puz q13po11) suoxe le.raqdr.rad ur ,(lzluaurrradxa paleaJc flls?a sI alzls sIqJ '.fi5rqrssod pcllaroaqt osp st pazr.telodap..rad,{q sr au?Jquaur Jelnllas aql qclqm ul" uortcntls alrsoddo aqa 'd11c1lseds ul algl u s.{u1d oslz lr leql sr a,rar,r u,v'o,(ur uoszeJ sn[] JoJ .a1nor cqdeu,(s -ouou aql {q sarcuenba:; q8rq lz saslndurr a8reqcsrp s.lotdacar 681 NOIJCV CrrJVN,f S NO NOIMlIUOJNI .gCISNt, l4O CHARLES scoTT SHERRINGToN 'natural' modes of stimulation. Their most important hlpothe- sis is that one afferent system may cause 'preslmaptic in- hibition' at the tenninals oi another, from which *Luld folto* that there might be synapses on the terminals themselves engaged in depolarizing their membranes. Wall's findings would possibly have received scant attention had not Frank and Fuortes ( 1957) by the intracellular technique been able to demonstrate that 'inhibition' in the sense oi a diminution of excitatory postsyraptic potentials could be obtained without change of resting membrane potential. Since postsynaptic inhibition is an increase of membrane potential, by what mechanism was this 'diminution of excitation' brought about I Frank and Fuortes called it 'remote inhibition, ;nd Eccles identifies it with the presynaptic depolarization of the terminals, to which his group has lately devoted so much .remote experimental work. Is the existence of real inhibition, thereby excluded and finally relegated to the realm of pre- synaptic depolarizations I It is too early to reply to this question in the affirmative. We know far too litt]e ibbut the ciremical side of the s5maptic mechanism, nor has pure dendritic excitation been sufficiently explored. Historically 'preslmaptic inhibition' is an offshoot of the line of-thought for which Lucas became responsible when he ascribed inhibitionto a blocking process such aJ the Wedensky inhibition at the end-plates caused by high-frequency tetanizition of the motor nerve. When Gasser studied the excitabilitv chanses following trains of impulses in the peripheral ,erve, ie wrs ied to think of inhibition along similar linis. Llovd,s study of the monos;maptic reflex and 'direct inhibition, may be said"to have re-installed the ideas of Sherrington. presynaptic inhibition has always had a number of talented advocates ( Gasser, Matthews, 'intraceliular Bremer, Wall) but until the advent of the micro_ electrode its champions have not had much ofa chance to expand beyond plausibilities. And why should it not be plausibie to assume that inhibition of a motoneurone could be the conse- quence of diminution of excitation owing to a block somewhere in the path I Assume this path to be one r.ihich projects exclusive_ Iy on to the dendrites. Can we then be quite clrtain that the in_tracellular microelectrode in the soma really is capable of reflecting this distant event by an increase of m-embrane poten_ 'uIopguDl Frrrru? eql lnoq8norql sllac a^Jau ul punoJ uaaq acus seq qcrq,!\ ssacord crldzu,(s1sod .salccg o1 uolllqlqul urrel aq] tclrtsar ol alq?sr^pe aq sdeqrad ppo.tr U a:e ,{aqt teq^\ sE pauJal .{pcarroc aro[r o.r? f,1r1qz11cxa Jo ses?aJcul Surpuodsa.uoc alrq,{r. .uoqrqrqul, u" se peqrJcsap sr LI upq} palJasqo f,r1lqrrlr*n uortonpar ? sr rauoos ou tzql Su1sryuoc allrll osp sl lI Jo " i IeB I+I NOIJSV SIrdVNr.S NO NOITYtr^IXOdNI .3ClSNI,