10

Overview of Synaptic Tr,

Syn.apses Are Either Electrical or Chemical

Electrical Syn.apses Provide Instantaneous Signal1I:ansmission

Gap-Junction Channels Connect Communicating Cells atan Electrical Synapse

Electrical Transmission Allows the Rapid andSynchronous Firing of Interconnected Cells

Gap Junctions Have a Role in Glial Function and Disease

Chemical Synapses Can Amplify Signals

Chemical Transmitters Bind to Postsynaptic Receptors

Postsynaptic Receptors Gate Ion Channels Either Directlyor Indirectly

W HAT GIVES NERVE CELLS their special ability tocommunicate with one another so rapidly,over such great distances, and with such

tremendous precision? We have already seen how sig-nals are propagated within a neuron, from its dendritesand cell body to its axonal terminal. Beginning with thischapter we consider the cellular mechanisms for signal-ing between neurons. The point at which one neuroncommunicates with another is called a synapse, andsynaptic transmission is fundamental to many of theprocesses we consider later in the book, such as percep-tion, voluntary movement, and learning.

The average neuron forms about 1000 synaptic con-nections and receives even more, perhaps as many as10,000 connections. The Purkinje cell of the cerebellumreceives up to 100,000 inputs. Although many of theseconnections are highly specialized, all neurons makeuse of one of two basic forms of synaptic transmission:

10

Overview of Synaptic Transmission

electrical or chemical. Moreover, the strength of bothforms of synaptic transmission can be enhanced or di-minished by cellular activity. This pblsticity in nerve cellsis crucial to memory and other higher brain functions.

In the brain, electrical synaptic transmission israpid and rather stereotyped. Electrical synapses areused primarily to send simple depolarizing signals;they do not lend themselves to producing inhibitory ac-tions or making long-lasting changes in the electricalproperties of postsynaptic cells. In contrast, chemicalsynapses are capable of more variable signaling andthus can produce more complex behaviors. They canmediate either excitatory or inhibitory actions in post-synaptic cells and produce electrical changes in thepostsynaptic cell that last from milliseconds to manyminutes. Chemical synapses also serve to amplify neu-ronal signals, so that even a small presynaptic nerve ter-minal can alter the response of a large postsynaptic cell.Because chemical synaptic transmission is so central tounderstanding brain and behavior, it is examined in de-tail in Chapters 11, 12, and 13.

Synapses Are Either Electrical or Chemical

The term synapse was introduced at the turn of the cen-tury by Charles Sherrington to describe the specializedzone of contact at which one neuron communicates withanother; this site had first been described histologically(at the level of light microscopy) by Ram6n y Cajal. Ini-tially, all synapses were thought to operate by means ofelectrical transmission. In the 1920s, however, OttoLoewi showed that acetylcholine (ACh), a chemical com-pound, conveys signals from the vagus nerve to the

176 Part m / Elementary Interactions Between Neurons: Synaptic Thansmission

Table 10-1 Distinguishing Properties of Electrical and Chemical Synapses

Distance betweenpre- andpostsynaptic cellmembranes

Type of

synapse

3.5nm

20-40 nm

Electrical

Chemical

heart. Loewi's discovery in the heart provoked consid-erable debate in the 193Os over how chemical signalscould generate electrical activities at other synapses, in-cluding nerve-muscle synapses and synapses in thebrain.

Two schools of thought emerged, one physiologicaland the other pharmacological. Each championed a sin-gle mechanism for all synaptic transmission. The physi-ologists, led by John Eccles (Sherrington's student), ar-gued that all synaptic transmission is electrical, that theaction potential in the presynaptic neuron generates acurrent that flows passively into the postsynaptic cell.The pharmacologists, led by Henry Dale, argued thattransmission is chemical, that the action potential in thepresynaptic neuron leads to the release of a chemicalsubstance that in turn initiates current flow in the post-synaptic cell.

A Current flow at electrical

Figure 10-1 Current flows differently at electrical and chem-ical synapses.A. At an electrical synapse some of the current injected into apresynaptic cell escapes through resting ion channels in thecell membrane. However, some current also flows into thepostsynaptic cell through specialized ion channels. called gap-junction channels, that connect the cytoplasm of the pre- andpostsynaptic cells.

Cytoplasmiccontinuitybetween pre- andpostsynaptic cells

Agent oftransmission

Synapticdelay

Direction oftransmission

Ultrastructuralcomponents

Ion currentYes

No

Usuallybidirectional

Unidirec-tional

Gap-junctionchannels

Vtrtuallyabsent

Chemicaltransmitter

Presynapticvesicles andactive zones;

postsynapticreceptors

Significant:at least 0.3IDS, usually1-5 IDSor longer

When physiological techniques improved in the19508 and 1960s it became clear that both forms of trans-mission exist. Although most synapses use a chemicaltransmitter, some operate purely by electrical means.Once the fine structure of synapses was made visiblewith the electron microscope, chemical and electricalsynapses were found to have different morphologies. Atchemical synapses neurons are separated completely bya small space, the synaptic cleft. There is no continuitybetween the cytoplasm of one cell and the next. In con-trast, at electrical synapses the pre- and postsynapticcells communicate through special channels, the gap-junction channels, that serve as conduits between the cy-toplasm of the two cells.

The main functional properties of the two types ofsynapses are summarized in Table 10-1. The most im-portant differences can be observed by injecting current

B Current flow at chemical synapsessynapses

I

Presyneptjc Postsynaptic

B. At chemical synapses all of the injected current escapesthrough ion channels in the presynaptic cell. However, the re-sulting depolarization of the cell activates the release of neuro-transmitter molecules packaged in synaptic vesicles (open cir-clesl, which then bind to receptors on the postsynaptic cell.This binding opens ion channels, thus initiating a change inmembrane potential in the postsynaptic cell.

I

I

j1

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1

c

t

t

14

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tJ

tJ

c

D

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it

ti

t1

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ta

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01

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A Experimental setup

PresYl18ptic neuron:Ieter8I gie~ fiber

Figure 10-2 Electrical synaptic transmission was firstdemonstrated to occur at the giant motor synapse in thecrayfish. (Adapted from Furshpan and Potter 1957 and 1959.)A. The presynaptic neuron is the lateral giant fiber runningdown the nerve cord. The postsynaptic neuron is the motorfiber. which projects from the cell body in the ganglion to theperiphery. The electrodes for passing current and for recording

into the presynaptic cell to elicit a signal (Figure to-t).At both types of synapses the current flows outwardacross the presynaptic cell membrane. This current de-posits a positive charge on the inside of the presynapticcell membrane, reducing its negative charge andthereby depolarizing the cell (see Chapter 8).

At electrical synapses the gap-junction channelsthat connect the pre- and postsynaptic cells provide alow-resistance (high conductance) pathway for electri-cal current to flow between the two cells. Thus, some ofthe current injected in the presynaptic cell flowsthrough these channels into the postsynaptic cell. Thiscurrent deposits a positive charge on the inside of themembrane of the postsynaptic cell and depolarizes it.The current then flows out through resting ion channelsin the postsynaptic cell (Figure to-tA). H the depolariza-tion exceeds threshold, voltage-gated ion channels inthe postsynaptic cell will open and generate an actionpotential.

At chemical synapses there is no direct low-resis-tance pathway between the pre- and postsynaptic cells.Thus, current injected into a presynaptic cell flows outof the cell's resting channels into the synaptic cleft, thepath of least resistance. Uttle or no current crosses the

Chapter 10 I Overview of Synaptic Transmission 177

CurrentInjection

Recordng ----

Iecording

Cutr8nt~injection

voltage are placed within both the p(f~ and postsynaptic cells.B. Transmission at an electrical synapse is virtually instant&-neous-the postsynaptic response follows presynaptic stimula-tion in a fraction of a millisecond. The dashed line shows howthe responses of the two cells correspond in time. In contrast.at chemical synapses there ia a delay between the pre- andpostsynaptic potentials (see Figure 1~7).

external membrane of the postsynaptic ceIL which has ahigh resistance (Figure 10-1B). Instead, the action poten-tial in the presynaptic neuron initiates the release of achemical transmitter, which diffuses across the synapticcleft to interact with receptors on the membrane of thepostsynaptic cell. Receptor activation causes the cell ei-ther to depolarize or to hyperpolarize.

Electrical Synapses Provide InstantaneousSignal Transmission

At electrical synapses the current that depoJarizes thepostsynaptic cell is generated directly by the voltage-gated ion channels of the presynaptic cell. Thus thesechannels not only have to depolarize the presynapticcell above the threshold for an action potential, theymust also generate sufficient ionic current to produce achange in potential in the postsynaptic cell. To generatesuch a large current, the presynaptic terminal has to belarge enough for its membrane to contain a large num-ber of ion channels. At the same time, the postsynapticcell has to be relatively small. This is because a small cellhas a higher input resistance (RiD) than a Iarse cell ArnI,

178 Part m / Elementary interactiON Between Neurons:

~ Current pulse to~ L. presyneptic cell

~ Volt8ge recordedJ \... In presyneptic cell

Agur. 10-3 Electrical transmission is graded and occurseven when the currents In the presynaptic cell are belowthe threshold for an ection potential. This can be demon-strated by depolarizing the presynaptic cell with a small out-ward current pulse. Current is passed by one electrode whilethe membrane potential is recorded with a second electrode.A subthreshold depolarizing stimulus causes a passive depolar-ization In the presynaptic and postsynaptic cells. (Outward,depolarizing current is indicated by upward deflection.)

according to Ohm's law (I1V" tJ x Rjn), will undergo agreater voltage change (11 V) in response to a givenpresynaptic current (tJ).

Electrical synaptic transmission was first describedin the giant motor synapse of the crayfish, where thepresynaptic fiber is much larger than the postsynapticfiber (Figure to-2A). An action potential generated inthe presynaptic fiber produces a depolarizing post-synaptic potential that is often large enough to dis-charge an action potential. The lIltency-the time be-tween the presynaptic spike and the postsynapticpotential-is remarkably short (Figure to-2B).

Such a short latency is incompatible with chemicaltransmission, which requires several biochemical steps:release of a transmitter from the presynaptic neuron,diffusion of the transmitter to the postsynaptic cell,binding of the transmitter to a specific receptor, andsubsequent gating of ion channels (all described later inthis chapter). Only current flowing directly from onecell to another can produce the near-instantaneoustransmission observed at the giant motor synapse.

Further evidence for electrical transmission is thatthe change in potential of the postsynaptic cell is di-rectly related to the size and shape of the change in p0-tential of the presynaptic cell. At an electrical synapseany amount of current in the presynaptic cell triggers aresponse in the postsynaptic cell. Even when a sub-threshold depolarizing current is injected into the pre-synaptic neuron, current flows into the postsynaptic cell

TransmissionSynaptic

and depolarizes it (Figure 10-3). In contrast, at a chemi-cal synapse the presynaptic current must reach thethreshold for an action potential before the cell can re-lease transmitter.

Most electrical synapses will transmit both depolar-izing and hyperpolarizing currents. A presynapticaction potential that has a large hyperpolarizingafterpotential will produce a biphasic (depolarizing-hyperpolarizing) change in potential in the postsynapticcell. Transmission at electrical synapses is similar to thepassive electrotonic propagation of subthreshold electri-cal signals along axons (see Chapter 8) and therefore isoften referred to as electrotonic transmission. Electrotonictransmission has been observed even at junctionswhere, unlike the giant motor synapse of the cray-fish, the pre- and postsynaptic elements are similar insize. Because signaling between neurons at electricalsynapses depends on the passive electrical properties atthe synapse, such electrical synapses can be bidirec-tional, transmitting a depolarization signal equally wellfrom either cell.

Gap-junction Channels Connect CommunicatingCells at an Electrical Synapse

Electrical transmission takes place at a specialized re-gion of contact between two neurons termed the gapjunction. At electrical synapses the separation betweentwo neurons is much less (3.5 nm) than the normal, non-synaptic space between neurons (20 nm). This narrowgap is bridged by the gap-junction dulnnels, specializedprotein structures that conduct the flow of ionic currentfrom the presynaptic to the postsynaptic cell (Figure10-4).

All gap-junction channels consist of a pair ofhemichannels, one in the presynaptic and the other in thepostsynaptic cell. These hemichannels make contact inthe gap between the two cell membranes, forming acontinuous bridge between the cytoplasm of the twocells (Figure 10-4A). The pore of the channel has a largediameter of around 1.5 nm, and this large size permitssmall intracellular metabolites and experimental mark-ers such as fluorescent dyes to pass between the twocells.

Each hemichannel is called a connexon. A connexonis made up of six identical protein subunits, called con-nexins (Figure 10-4B). Each connexin is involved in twosets of interactions. First, each connexin recognizes theother five connexins to form a hemichannel. Second,each connexin of a hemichannel in one cell recognizesthe extracellular domains of the apposing connexin ofthe hemichannel of the other cell to form the conductingchannel that connects the two cells.

/

6 connexin subunits .1 connexon (hemich8nnell

~

Chapter 10 / Overview of 179Synaptic Transmission

<It'"

"..,,"

,,'",,'

..'"

",/'

~""..,;

Figure 10-4 A three-dimensional model ofthe gap-junction channel, based on X-rayand electron diffraction studies.A. At electrical synapses two cells are struc-turally connected by gap-junction channels.A gap-junction channel is actually a pair ofhemichannels, one in each apposite cell, thatmatch up in the gap junction throughhomophilic interactions. The channel thus con-nects the cytoplasm of the two cells and pro-vides a direct means of ion flow between thecells. This bridging of the cells is facilitated by anarrowing of the normal intercellular space(20 nm) to only 3.5 nm at the gap junction.(Adapted from Makowski et al. 1977.)Electron micrograph: The array of channelsshown here was isolated from the membraneof a rat liver. The tissue has been negativelystained, a technique that darkens the areaaround the channels and in the pores. Eachchannel appears hexagonal in outline. Magnifi-cation x 307,800. (Courtesy of N. Gilula.)

Normalextracellularspace

Ch8meI formedbvporesin88d1 membr8ne

&ch 01 the 15 connexinshas .. membr8ne-spenningregions

B. Each hemichannel, or connexon, is made upof six identical protein subunits called connex-ins. Each connexin is about 7.5 nm long andspans the cell membrane. A single connexin isthought to have four membranErSpanning re-gions. The amino acid sequences of gap-junction proteins from many different kinds oftissue all show regions of similarity. In particu-lar, four hydrophobic domains with a high de-gree of similarity among different tissues arepresumed to be the regions of the proteinstructure that traverse the cell membrane. Inaddition, two extracellular regions that are alsohighly conserved in different tissues arethought to be involved in the homophilic match-ing of apposite hemichannels.

C. The connexins are arranged in such a waythat a pore is formed in the center of the struc-ture. The resulting connexon, with an overall di-ameter of approximately 1.5-2 nm, has a char-acteristic hexagonal outline, as shown in theelectron micrograph in A. The pore is openedwhen the subunits rotate about 0.9 nm at thecytoplasmic base in a clockwise direction.(From Unwin and Zampighi 1980.)

Cytopllsmic loopsfor regulation

ExtraceIIulirIp8C8

Extracellular loops forhemophilic interactions,

~

180 Part ill / Elementary Interactions Between Neurons: Synaptic Transmission

Connexins from different tissues all belong to onelarge gene family. Each connexin subunit has fourhydrophobic domains thought to span the cell mem-brane. These membrane-spanning domains in the gap-junction channels of different tissues are quite similar, asare the two extracellular domains thought to be in-volved in the homophilic recognition of the hemichan-nels of apposite cells (Figure lo-4C). On the other hand,the cytoplasmic regions of different connexins varygreatly, and this variation may explain why gap junc-tions in different tissues are sensitive to different modu-latory factors that control their opening and closing.

For example, most gap-junction channels close inresponse to lowered cytoplasmic pH or elevated cyto-plasmic CaH. These two properties serve to decoupledamaged cells from other cells, since damaged cells con-tain elevated ea2+ and proton concentrations. At somespecialized gap junctions the channels have voltage-dependent gates that permit them to conduct depolariz-ing current in only one direction, from the presynapticcell to the postsynaptic cell. These junctions are calledrectifying synapses. (The crayfish giant motor synapse isan example.) Finally, neurotransmitters released fromnearby chemical synapses can modulate the opening ofgap-junction channels through intracellular metabolicreactions (see Chapter 13).

How do the channels open and close? One sugges-tion is that, to expose the channel's pore, the six connex-ins in a hemichannel rotate slightly with respect to oneanother, much like the shutter in a camera. The con-certed tilting of each connexin by a few Angstroms atone end leads to a somewhat larger displacement at theother end (Figure lO-4B). As we saw in Chapter 7, con-formational changes in ion channels may be a commonmechanism for opening and closing the channels.

Electrical Transmission Allows the Rapid andSynchronous Firing of Interconnected Cells

Why is it useful to have electrical synap~? As we haveseen, transmission across electrical synapses is ex-tremely rapid because it results from the direct flow ofcurrent from the presynaptic neuron to the postsynapticcell. And speed is important for certain escape re-sponses. For example, the tail-flip response of goldfishis mediated by a giant neuron (known as Mauthner'scell) in the brain stem, which receives input from sen-sory neurons at electrical synapses. These electricalsynapses rapidly depolarize the Mauthner's cell, whichin turn activates the motor neurons of the tail, allowingthe fish to escape quickly from danger.

Electrical transmission is also useful for connectinglarge groups of neurons. Because current flows across

the membranes of all electrically coupled cells at thesame time, several small cells can act coordinately asone large cell. Moreover, because of the electrical cou-pling between the cells, the effective resistance of thecoupled network of neurons is smaller than the resis-tance of an individual cell. As we have seen from Ohm'slaw (A V = AI X R), the lower the resistance of a neuron,the smaller the depolarization produced by an excita-tory synaptic current. Thus, electrically coupled cells re-quire a larger synaptic current to depolarize them tothreshold, compared with the current that would benecessary to fire an individual cell. This property makesit difficult to cause them to fire action potentials. Oncethis high threshold is surpassed, however, electricallycoupled cells tend to fire synchronously because activeNa + currents generated in one cell are rapidly transmit-

ted to the other cells.Thus, a behavior controlled by a group of electri-

cally coupled cells has an important adaptive advan-tage: It is triggered explosively in an all-or-none man-ner. For example, when seriously perturbed, the marinesnail Aplysia releases massive clouds of purple ink thatprovide a protective screen. This stereotypic behavior ismediated by three electrically coupled, high-thresholdmotor cells that innervate the ink gland. Once thethreshold for firing is exceeded in these cells, they firesynchronously (Figure 10-5). In certain fish, rapid eyemovements (called saccades) are also mediated by elec-trically coupled motor neurons acting synchronously.

In addition to providing speed or synchrony in neu-ronal signaling, electrical synapses also may transmitmetabolic signals between cells. Because gap-junctionchannels are relatively large and nonselective, theyreadily allow inorganic cations and anions to flowthrough. In fact, gap-junction channels are large enoughto allow moderate-sized organic compounds (less than1000 molecular weight~ch as the second messen-gers IP3 (inositol triphosphate), cAMP, and even smallpeptides-to pass from one cell to the next.

Gap Junctions Have a Role in GlialFunction and Disease

Gap junctions are found between glial cells as well asbetween neurons. In glia the gap junctions seem to me-diate both intercellular and intracellular communica-tion. The role of gap junctions in signaling between glialcells is best observed in the brain, where individual as-trocytes are connected to each other through gap junc-tions, forming a glial cell network. Electrical stimulationof neuronal pathways in brain slices can trigger a rise ofintracellular Ca2+ in certain astrocytes. This produces awave of intracellular Ca2+ throughout the astrocyte net-

Figure 10-5 Electrically coupled motorneurons firing together can produceinstantaneous behaviors. The behaviorillustrated here is the release of a protec-tive cloud of ink by the marine snailAplysiB. (Adapted from Carew and Kandel1976.)A. Sensory neurons from the tail ganglionform synapses with three motor neuronsthat project to the ink gland. The motorneurons are interconnected by means ofelectrical synapses.B. A train of stimuli applied to the tail pro-duces a synchronized discharge in allthree motor neurons. 1. When the motorneurons are at rest the stimulus triggersa train of identical action potentials in allthree cells. This synchronous activity inthe motor neurons results in the releaseof ink. 2. When the cells are hyperpolar-ized the stimulus cannot trigger actionpotentials, because the cells are too farfrom their threshold level. Under theseconditions the inking response isblocked.

Chapter 10 / Overview of Synaptic Transmission 181

A Neural circuit of the inking response

B Motor cell responses to tail stimulation

1 Cells at rest 2 Cells hyperpolarized

R8IeIseof Ink

........of ink

A

c

182 Part ill / Elementary Interactions Between Neurons: Synaptic Transmission

work, traveling at a rate of around 1 JLn'l/ms. TheseCa2+ waves are believed to propagate by diffusionthrough gap-junction channels. Although the precisefunction of such Ca2+ waves is not known, their exis-tence clearly suggests that glia may play an active rolein signaling in the brain.

Evidence that gap junctions enhance communica-tion within a single glial cell is found in Schwann cellsof the myelin sheath. As we have seen in Chapter 4, suc-cessive layers of myelin are connected by gap junctions,which may serve to hold the layers of myelin together.However, they may also be important for passing smallmetabolites and ions across the many intervening layersof myelin, from the outer perinuclear region of theSchwann cell down to the inner periaxonal region. Theimportance of these gap-junction channels is under-scored by certain neurological genetic diseases. For ex-ample, the X chromosome-linked form of Charcot-Marie- Tooth disease, which causes demyelination,results from single mutations in one of the connexingenes (connexin32) expressed in the Schwann cell. Suchmutations prevent this connexin from forming func-tional gap-junction channels essential for the normalflow of metabolites in the Schwann cell.

Chemical Synapses Can Amplify Signals

In contrast to the situation at electrical synapses, there isno structural continuity between pre- and postsynapticneurons at chemical synapses. In fact, at chemicalsynapses the region separating the pre- and postsynap-tic cells-the synaptic cleft-is usually slightly wider(20-40 nm), sometimes substantially wider, than the ad-jacent nonsynaptic intercellular space (20 nm). As a re-sult, chemical synaptic transmission depends on the re-lease of a neurotransmitter from the presynapticneuron. A neurotransmitter is a chemical substance thatwill bind to specific receptors in the postsynaptic cellmembrane. At most chemical synapses, transmitter re-lease occurs from presynaptic termiruzls, specializedswellings of the axon. The presynaptic terminals containdiscrete collections of synaptic vesicles, each of which isfilled with several thousand molecules of a specifictransmitter (Figure 10-6).

The synaptic vesicles cluster at regions of the mem-brane specialized for releasing transmitter called activezones. During discharge of a presynaptic action potentialCa2+ enters the presynaptic terminal through voltage-gated Ca2+ channels at the active zone. The rise in intra-cellular Ca2+ concentration causes the vesicles to fusewith the presynaptic membrane and thereby releasetheir neurotransmitter into the synaptic cleft, a process

termed exocytosis.The transmitter molecules then diffuse across the

synaptic cleft and bind to their receptors on the postsyn-aptic cell membrane. This in turn activates the receptors,leading to the opening or closing of ion channels. Theresulting ionic flux alters the membrane conductanceand potential of the postsynaptic cell (Figure 10-7).

These several steps account for the synaptic delayat chemical synapses, a delay that can be as short as0.3 ms but often lasts several milliseconds or longer. Al-though chemical transmission lacks the speed of electri-cal synapses, it has the important property of amplifica-tion. With the discharge of just one synaptic vesicle,several thousand molecules of transmitter stored in thatvesicle are released. lYPically, only two molecules oftransmitter are required to open a single postsynapticion channel. Consequently, the action of one synapticvesicle can open thousands of ion channels in the post-synaptic cell. In this way a small presynaptic nerve ter-minal, which generates only a weak electrical current,can release thousands of transmitter molecules that candepolarize even a large postsynaptic cell.

~

Figure 10-8 The synaptic cleft separates the presynapticand postsynaptic cell membranes at chemical synapses.This electron micrograph shows the fine structure of a presyn-aptic terminal in the cerebellum. The large dark structures aremitochondria. The many round bodies are vesicles that containneurotransmitter. The fuzzy dark thickenings along the presy-naptic side of the cleft (arrows) are specialized areas, called ac-tive zones, that are thought to be docking and release sites forvesicles. (Courtesy of J. E. Heuser and T. S. Reese.)

rPresynapticection potenti8l

mV~

0

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Excitatorypoetsynepticpotential ~~rrN

--[=-70 H, I'ftI

Rgure 10-7 Synaptic transmission at chemical synapses in-volves several steps. An action potential arriving at the termi-nal of a presynaptic axon causes voltage-gated Ca2+ channelsat the active zone to open. The influx of Ca2+ produces a highconcentration of Ca2+ near the active zone. which in tumcauses vesicles containing neurotransmitter to fuse with thepresynaptic cell membrane and release their contents into thesynaptic cleft (a process termed exocytosis). The releasedneurotransmitter molecules then diffuse across the synaptic

Chemical Transmitters Bindto Postsynaptic Receptors

Chemical synaptic transmission can be divided into twosteps: a transmitting step, in which the presynaptic cellreleases a chemical messenger, and a receptive step, inwhich the transmitter binds to the receptor molecules inthe postsynaptic cell.

The transmitting process resembles the releaseprocess of an endocrine gland, and chemical synaptictransmission can be seen as a modified form of hormonesecretion. 80th endocrine glands and presynaptic termi-nals release a chemical agent with a signaling function,and both are examples of regulated secretion (Chapter4). Similarly, both endocrine glands and neurons areusually some distance from their target cells. There isone important difference, however. The hormone re-leased by the gland travels through the blood streamuntil it interacts with all cells that contain an appropri-ate receptor. A neuron, on the other hand, usually com-municates only with specific cells, the cells with which itforms synapses. Communication consists of a presynap-tic neuron sending an action potential down its axon tothe axon terminal, where the electrical signal triggers

Chapter 10 / Overview of Synaptic Transmission 183

cr. entry taunlY8IicIe fusion andtrlnlfT1itl8r ........

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nerve ten}'linal

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cleft and bind to specific receptors on the post-synaptic mem-brane. These receptors cause ion channels to open (or close).thereby changing the membrane conductance and membranepotential of the postsynaptic cell. The complex process ofchemical synaptic transmission is responsible for the delay be-tween action potentials in the pre- and post-synaptic cells ~pared with the virtually instantaneous transmission of signals atelectrical synapses (see Figure 10-28). The gray filaments rep-resent the docking and release sites of the active zone.

the focused release of the chemical transmitter onto atarget cell. Thus the chemical signal travels only a smalldistance to its target. Neuronal signaling, therefore, hastwo special features: It is fast and precisely directed.

To accomplish this highly directed or focused re-lease, most neurons have specialized secretory machin-ery, the active zones. In neurons without active zonesthe distinction between neuronal and hormonal trans-mission becomes blUrred. For example, the neurons inthe autonomic nervous system that innervate smoothmuscle reside at some distance from their postsynapticcells and do not have specialized release sites in theirterminals. Synaptic transmission between these cells isslower and more diffuse. Furthermore, at one set of ter-minals a transmitter can be released at an active zone, asa conventional transmitter acting directly on neighbor-ing cells; at another locus it can be released in a less fo-cused way as a modulator, producing a more diffuse ac-tion; and at a third locus it can be released into the bloodstream as a neurohormone.

Although a variety of chemicals serve as neuro-transmitters, including both small molecules and pep-tides (see Chapter 15), the action of a transmitter in the

184 Part ill / Elementary Interactions Between Neurons: Synaptic Transmission

A Direct gatingReceptor Pore

Transmitter I"Effectorfunction

~

a T a I

Figure 10-8 Neurotransmitters act either directly or indi-rectly on ion channels that regulate current flow in neu-rons.A. Direct gating of ion channels is mediated by ionotropic re-ceptors. This type of receptor is an integral part of the samemacromolecule that forms the channel it regulates and thus issometimes referred to as a receptor-<:hannel or ligand-gatedchannel. Many ionotropic receptors are composed of five sub-units, each of which is thought to contain four membrane-spanning a-helical regions (see Chapters 11, 12).

B. Indirect gating is mediated by activation of metabotropic re-ceptors. This type of receptor is distinct from the ion channels

postsynaptic cell does not depend on the chemical prop-erties of the transmitter but rather on the properties ofthe receptors that recognize and bind the transmitter.For example, acetylcholine (ACh) can excite some post-synaptic cells and inhibit others, and at still other cells itcan produce both excitation and inhibition. It is the re-ceptor that determines whether a cholinergic synapse isexcitatory or inhibitory and whether an ion channel willbe activated directly by the transmitter or indirectlythrough a second messenger.

Within a group of closely related animals a giventransmitter substance binds to conserved families of re-ceptors and is associated with specific physiologicalfunctions. For example, in vertebrates ACh producessynaptic excitation at the neuromuscular junction byacting on a special type of excitatory ACh receptor. Italso slows the heart by acting on a special type of in-hibitory ACh receptor.

The notion of a receptor was introduced in the late

B Indirect gating

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it regulates. The receptor activates a GTP-binding protein (Gprotein), which in tum activates a second-messenger cascadethat modulates channel activity. Here the G protein stimulatesadenylyl cyclase, which converts ATP to cAMP. The cAMP acti-vates the cAMP-dependent protein kinase (cAMP-kinase),which phosphorylates the channel (P), leading to a change infunction. (The action of second messengers in regulating ionchannels is described in detail in Chapter 13.) The typicalmetabotropic receptor is composed of a single subunit withseven membrane-spanning a-helical regions that bind theligand within the plane of the membrane.

nineteenth century by the German bacteriologist PaulEhrlich to explain the selective action of toxins and otherpharmacological agents and the great specificity of im-munological reactions. In 1900 Ehrlich wrote, "Chemicalsubstances are only able to exercise an action on the tissueelements with which they are able to establish an intimatechemical relationship. . . . [This relationship] must bespecific. The [chemical] groups must be adapted to oneanother. . . as lock and key." In 1906 the English phar-macologist John Langley postulated that the sensitivity ofskeletal muscle to curare and nicotine was caused by a"receptive molecule." A theory of receptor function waslater developed by Langley's students (in particular, EliotSmith and Henry Dale), a development that was based onconcurrent studies of enzyme kinetics and cooperativeinteractions between small molecules and proteins. Aswe shall see in the next chapter, Langley's "receptive mol-ecule" has been isolated and characterized as the ACh re-ceptor of the neuromuscular junction.

All receptors for chemical transmittersbiochemical features in common:

1. They are membrane-spanning proteins. The regionexposed to the external environment of the cell rec-ognizes and binds the transmitter from the pre-synaptic cell.

2 They carry out an effector function within the tar-get cell. The receptors typically influence the open-ing or closing of ion channels.

Postsynaptic Receptors Gate Ion ChannelsEither Directly or Indirectly

Chemical neurotransmitters act either directly or indi-rectly in controlling the opening of ion channels in thepostsynaptic cell. The two classes of transmitter actionsare mediated by receptor proteins derived from differ-ent gene families.

Receptors that gate ion channels directly, such asthe nicotinic ACh receptor at the neuromuscular junc-tion, are integral membrane proteins. Several subunitscomprise a single macromolecule that contains both anextracellular domain that forms the receptor for trans-mitter and a membrane-spanning domain that forms anion channel (Figure 10-8A). Such receptors are often re-ferred to as ionotropic receptors. Upon binding neuro-transmitter the receptor undergoes a conformationalchange that results in the opening of the channel Theactions of ionotropic receptors, also called receptor-channels or ligand-gated channels, are discussed ingreater detail in Chapter 11.

Receptors that gate ion channels indirectly, like theseveral types of norepinephrine or serotonin receptorsat synapses in the cerebral cortex, are macromoleculesthat are distinct from the ion channels they affect. Thesereceptors act by altering intracellular metabolic reac-tions and are often referred. to as metabotropic receptors.Activation of these receptors very often stimulates theproduction of second messengers, small freely diffusibleintracellular metabolites such as cAMP and diacylglyc-eroL Many such second messengers activate protein ki-nases, enzymes that phosphorylate different substrateproteins. In many instances the protein ldnases directlyphosphorylate ion channels, leading to their opening orclosing. The actions of the metabotropic receptor are ex-amined in detail in Chapter 13.

Ionotropic and metabotropic receptors have differ-ent functions. The ionotropic receptors produce rela-tively fast synaptic actions lasting only milliseconds.These are commonly found in neural circuits that medi-ate rapid behaviors, such as the stretch receptor reflex.The metabotropic receptors produce slower synaptic ac-

Chapter 10 / Overview of Synaptic Transmission 185

lions lasting seconds to minutes. These slower actionscan modulate behavior by altering the excitability ofneurons and the strength of the synaptic connections ofthe neural circuitry mediating behavior. Such modula-tory synaptic pathways often act as crucial reinforcingpathways in the process of learning.

Eric R. KandelSteven A. Siegelbaum

Selected Readings

Bennett MY. 1997. Gap junctions as electrical synapses.J Neurocytol 26:349-366.

Eccles Je. 1976. From electrical to chemical transmission inthe central nervous system. The closing address of the SirHenry Dale Centennial Symposium. Notes Rec R SacLond 30-.219-230.

Furshpan BI, Potter DD. 1959. Thmsmission at the giant mo-tor synapses of the crayfish. J Physiol (Lond) 145:289-325.

Goodenough DA, Go1iger JA, Paul DL. 1996. Connexins,connexons, and intercellular communication. Ann RevBiochem 65:475-502.

Jesse1l 'I'M, Kandel ER. 1993. Synaptic transmission: a bi-directional and a self-modifiable form of cell-cell commu-nication. Ce1l72(Suppl):1-30.

Unwin N. 1993. Neurotransmitter action: opening of ligand-gated ion channels. Ce1l72(Suppl):31-41.

References

Beyer Ee, Paul DL, Goodenough DA. 1987. Connexin43: aprotein from rat heart homologous to a gap junction pr0-tein from liver. J Cell Bioi 105:2621-2629.

Bruzzone It White lW, Scherer 55, Fischbeclc KH, PaulDL. 1994. Null mutations of connexin 32 in patientswith x-linked Charcot-Marie- Tooth disease. Neuron13:1~1260.

Carew 1}, Kandel ER. 1976. 1Wo functional effects of de-creased conductance EPSP's: synaptic augmentation andincreased electrotonic coupling. Science 192:15(}-153.

Cornell-Bell AH, Finkbeiner SM, Cooper MS, Smith 51. 1990.Glutamate induces calcium waves in cultured astrocytes:long-range glial signaling. Science 247:470-473.

Dale H. 1935. Pharmacology and nerve-endings. Proc R SacMed (Lond) 28:319-332.

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Ehrlich P. 1900. On immunity with special reference to celllife. Croo1Uan Lect Proc R Soc Land 66:424-448.

185

have two

Eric R. KandelA. SiegelbaumSteven

186 Part ill / IDementary Interactions Between Neurons: Synaptic Transmission

Furshpan BI, Potter 00.1957. Mechanism of nerve-impulsetransmission at a crayfish synapse. Nature 180:342-343.

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