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Home , Chemical synapse

CHAPTER 13

SYNAPSES

he consists of billions possess a swelling at their ends. The of , each one an individual boutons, whether from myelinated or Tcell, receiving signals from some unmyelinated fibers, are always found in other cells and generating signals of its own close proximity to a , , or to be sent to other cells. We consider here of another or to another bouton. how these signals are transferred from one At the site of the termination of a fiber, to another. In most cases, there is a the specializations of the terminal and the gap between neurons that must be bridged in cell it contacts are called collectively a order for transmission to continue . on somas are termed throughout the nervous system. In some axosomatic synapses; those on are cases, there appears to be no gap between termed axodendritic; and those on other or boutons are axoaxonic. The fiber's bouton is called the presynaptic element and the structure it contacts is the postsynaptic element. A schematic diagram of a synapse is shown in Figure 13- 1A. The pre- and postsynaptic elements are separated by a space 15-200 nm wide, known as the synaptic cleft. At the synapse, the membrane of the postsynaptic Figure 13-1A. A schematic diagram of a synapse indicating elementthe pre- is slightly thickened, and there is and postsynaptic elements with synaptic specializations.

the neurons. Transmission between cells connected in this way is believed to occur by purely electrical events. How these two kinds of transmission occur is the subject of this chapter.

Anatomy of a synapse. If we follow a primary afferent fiber along its course, we find that the fiber may branch many times, becoming smaller each time. If the fiber is myelinated, then near its Figure 13-1B. A electron micrograph a synapse termination the disappears and there showing the pre- and postsynaptic elements with synaptic specializations. Note the accumulation of is a swelling of the axon, called the bouton mitochondria and presence of synaptic vesicles in terminaux, end bulb, terminal, synaptic the presynaptic membrane. The actual points of knob, or just bouton; with this swelling, the synaptic contact are indicated by the arrows. fiber simply ends. Unmyelinated fibers also

13-1 often an accumulation of some electron- inactivation of the released dense (appears dark in electron micrographs) transmitter substance, i.e., it must be material near the thickened membrane. On degraded or taken-up again by the the presynaptic side, there is normally an terminal, accumulation of mitochondria in the bouton 4. A synaptic action must be identified and, in electron micrographs, a large number for the substance, and local of spherical or irregularly shaped structures application must produce effects are seen near the synaptic region. These are "exactly" like those of synaptically called synaptic vesicles. All of these released transmitter substance, structures except the synaptic cleft (you’d 5. Drugs must produce similar effects need a higher power to see that) are visible upon actions of the substance and in the electron micrograph of Figure 13-1B. natural transmitter substance. It is believed that transmission from one No one of these criteria is sufficient by cell to another at a synapse like the one just itself to define a transmitter substance. For described (a , as opposed example, a compound, present in to an ) is accomplished by terminals, could not be a transmitter release of a substance, the transmitter substance unless it was released and unless it substance, from the synaptic vesicles into influenced the postsynaptic cell. It is also the synaptic cleft by the process of exocyto- possible that a compound serves as a sis. The identity of the transmitter substance transmitter substance in one neuron, but is unknown for most synapses. Many serves a different purpose in another one. candidate transmitter substances have been Table 13-1 contains a list of some of the suggested; however, we can be certain a substances that have been suggested as substance is a transmitter substance only if it chemical transmitter substances, their meets all of the following criteria: presumed actions2, locations of highest 1. The substance must occur naturally concentration within the central nervous in presynaptic terminals, and either system, modes of action (we will have more the precursors and enzymes for its to say about this later), and agents that block formation or an adequate, specific their actions. transport system for its uptake into It is difficult to establish the validity of the terminal must exist, all five criteria at synapses within the central 2. The substance must be released from nervous system because the cells involved the terminals by nerve stimulation, can rarely be seen; because only small 3. A mechanism must exist for rapid1

1 How rapidly the transmitter substance must be hydrolyzed or removed from the 2 Some care should be exercised in synaptic is determined by the duration of attributing single actions to transmitter action of the natural transmitter substance. substances. , for example, is As we shall see, some transmitter substances usually thought of as excitatory, but there have only short actions; others act for long are some cases in which it is known to be times; some do both at different places. inhibitory.

13-2

Table 13-1 Known and Putative Transmitter Substances in the Mammalian Nervous System

Presumed Locations of maximum Mode of Substance action concentration action Blocking agents

Acetylcholine Excitation, Interpeduncular, dorsal raphe and Ionotropic, , atropine inhibition caudate nuclei, nucleus metabotropic accumbens, ventral horn of spinal (cGMP‡) cord

Glycine Inhibition Spinal cord, medulla, pons Ionotropic

(-aminobutyric acid Inhibition Cerebellum, , spinal Ionotropic Bicuculline cord,

Norepinephrine Excitation, Pons, medulla Metabotropic Propanolol, inhibition (cAMP†)

Dopamine Excitation, , caudate, locus ceruleus, Metabotropic Phenoxybenzamine inhibition hypothalamus (cAMP†)

Serotonin (5-HT) Excitation, Amygdala, hypothalamus, septum, ? LSD! inhibition striatum

L-Glutamate Excitation Temporal cortex, basal ganglia, Ionotropic ? cerebellum, amygdala

L-Aspartate Excitation , occipital cortex, Ionotropic ? thalamus, cerebellum, hypothalamus

Epinephrine ? Thalamus, hypothalamus Metabotropic Propanolol, (cAMP†) phentolamine

Substance P? Excitation Substantia nigra, trigeminal Metabotropic ? nucleus, dorsal horn of spinal cord, (?) limbic system

Enkephalins? Inhibition Globus pallidus, caudate, nucleus ? Naloxone accumbens, hypothalamus

Endorphins? Inhibition Pituitary, striatum, spinal cord ? Naloxone

Histamine Inhibition Hypothalamus, thalamus Metabotropic Ethanolamine, (cAMP†) butamide

Others: Taurine, neurotensin, carnosine, angiotensin II, hypothalamic releasing factors, serine, proline, N-acetyl- L-aspartate, adenosine, P-tyramine, tryptamine

? Peptides † cAMP = cyclic adenosine monophosphate ‡ cGMP = cyclic guanine monophosphate ! LSD = lysergic acid diethylamide

13-3 Table 13-2

Status of Putative Transmitter Substances s n i h p r o d d i c n a E

e

c n i + e i

r r n s y i P h t l n

i e e p e u e o l t n e e n c n b i h t a a i i n e n c a o n h i l t a n m m n o m p r p t i y i t a a a e a t s e c t t o r p e k p b m y u r s c o l l s o i n e u Criterion A A N ( - G G A D S S E H 1. Present in presynaptic % % % L % % % % % % % terminals–precursors and enzymes present 2. Released from terminals by nerve % % % x % % % % ? ? % impulses 3. Rapid inactivation mechanism % % % ? ? % ? % % ? ? 4. Known action–local application mimics % % % % ? % ? ? ? ? ? natural transmitter substance 5. Pharmacologically similar to natural % % % % ? % % ? ? ? ? transmitter substance Key: % = Property demonstrated L = Labeled substance is taken up by synapses in vitro or in vivo, but it is not know that synapses normally contain it x = Exogenous, labeled substance is released, but release of endogenous substance has not been shown ? = Property not examined experimentally or results hard to interpret quantities of transmitter substance are autonomic ganglia, and at some sympathetic released and even these are rapidly degraded and all parasympathetic postganglionic if they are not protected from enzyme action; synapses, NE at most sympathetic and because it is impossible to know if the postganglionic synapses, and at putative transmitter substance is being sympathetic ganglionic synapses. Table 13- applied near the postsynaptic membrane. 2 shows the validity of all five criteria for Thus, acetylcholine (ACh), these substances and for (-aminobutyric (NE) and dopamine (DA) have been acid (GABA), an inhibitory transmitter identified as transmitter substances at substance in the . synapses in the peripheral nervous system, The remaining compounds of Table 13-2 ACh at the , at all meet one or more of the five criteria. These

13-4 compounds must still be considered as accumulation of synaptic vesicles on what is putative transmitter substances though some presumed to be the presynaptic side of each people ignore the deficiencies and call them synapse. The function of this arrangement is transmitter substances. unknown. The physiology of these new synaptic arrangements has not been studied in detail yet, but it can be presumed for now that they behave like other chemical synapses. Their presence certainly broadens the possibilities for interactions between neurons in the central nervous system. Another type of synaptic arrangement that has received a great deal of attention is the electrotonic synapse or electrical synapse, the substrate for which is thought to be the . A schematic diagram of a gap junction (sometimes called a connexon) is shown in Figure 13-3. The membranes of the two cells involved come extremely close or may actually fuse together. X-ray diffraction studies suggest Figure 13-2. A reciprocal synaptic relationship between two dendrites. Note the that membrane ionic channels (perhaps accumulations of synaptic vesicles on what is sodium channels) of the two cells are in presumed to be the presynaptic side of the register such that there are small conduits synapses. between the two neurons by which their cytoplasms could communicate. Gap Several other types of connections junctions are most frequently seen in between cells have been discovered. These dendrodendritic, dendrosomatic, and junctions, thought to be substrates for somatosomatic synaptic arrangements, but chemical transmission, occur between two dendrites (dendrodendritic synapses), a dendrite and an axon (dendroaxonic synapses), a dendrite and a soma (dendro- somatic synapses), and any part of a neuron and a (nodal synapses). In some cases, synapses have been described in which a single element is both pre- and postsynaptic to a second element. This arrangement, a Figure 13-3. A schematic diagram of what is thought to be the structure of an electrical synapse. Note that the sodium channels of reciprocal synaptic arrangement, is the the membranes of the two cells are in register, forming a illustrated in Figure 13-2. Note the channel between the two cells.

13-5 they do occur in other types of synapses. region to fuse with the presynaptic Such junctions have been found in the membrane whereupon the fused membrane retina, olfactory bulb, cerebellar cortex, breaks and spills the contents of the vesicles lateral vestibular nuclei, inferior olive and into the synaptic cleft. The release of elsewhere, but they are also found outside transmitter substances depends upon several the nervous system. A role for gap junctions factors, including the magnitude of the in the control of cellular proliferation has hypopolarization, the number of available been suggested. vesicles, and, importantly, the concentration The majority of the synapses in the of calcium in the extracellular fluid. vertebrate central nervous system are of the Reduced calcium blocks synaptic axosomatic and axodendritic types and of transmission. Likewise, increased manga- the chemically transmitting type. It is nese, a calcium inhibitor, leads to depression therefore a small wonder that chemical or block of transmission. Calcium appears transmission is the most thoroughly to be necessary for hypopolarization-release understood. There are now many reports of coupling. Hypopolarization leads to opening gap junctions and presumed electrotonic of voltage-gated Ca++ channels and the entry coupling between neurons in vertebrates, of Ca++ into the terminal. Once inside, Ca++ especially in mammals. Yet, two important promotes fusion of the vesicles with the morphological questions still remain terminal membrane and release of the unanswered: (1) Is every structure that looks transmitter substance. The released like a chemical synapse really a chemical transmitter substance diffuses across the and not an electrical synapse, or for that cleft in a fraction of a millisecond and matter a synapse at all? (2) Is every gap interacts with the postsynaptic membrane, junction an electrical synapse and not a changing its permeability and, ultimately, chemical synapse, or for that matter a the at that point on the synapse at all? These questions are made postsynaptic membrane. The action of the important by the observations that vesicles transmitter substance is terminated by its (possibly synaptic vesicles) are found in removal from receptors on the postsynaptic conjunction with both chemical synapses membrane. Some transmitter substances are and gap junctions and that gap junctions are then degraded, e.g., acetylcholine, whereas characteristic of epithelia, in general, and not others are taken up by the presynaptic limited to the nervous system, which is terminal, e.g., norepinephrine and other epithelial in origin. It is not clear that amine transmitter substances. This entire answers to these questions are even possible. process, from presynaptic spike to the termination of the postsynaptic response, Physiology of a chemical synapse. frequently requires only 10-20 msec. An , initiated in an Most chemical transmitter substances act afferent axon, arrives at a bouton and by producing changes in the transmembrane hypopolarizes it. Boutons hypopolarize in potential of the postsynaptic cell. Some the same way as axons. At this point the produce their effects noticeably more slowly action potential itself can go no farther, but the hypopolarization of the bouton somehow causes some of the synaptic vesicles in the

13-6 At ganglionic synapses of the sympathetic nervous system acetylcholine has both a fast action (4 to 7-msec latency and a 200-msec duration) and a slow action (200 to 300- msec latency and a 5-sec or longer duration). Both effects occur on the same postsynaptic cell! The rapid-onset, briefer effects of acetylcholine at skeletal muscle are apparently the consequence of changed ionic conductances, resulting from conformational changes in the membrane. These Figure 13-4A. Model of ionotropic synaptic conformational changes result from the transmission. A transmitter substance binds to a interaction of the transmitter substance with and opens a channel, changing receptors3 in the postsynaptic membrane. membrane conductance and, therefore, membrane potential. This is called ionotropic transmission, and it is illustrated schematically in Figure 13-4A. The longer latency and duration of norepinephrine effects on sympathetic postsynaptic structures have been explained by invoking a second messenger, in this case, cyclic adenosine monophosphate (cAMP). The model proposed for this kind of transmission, called metabotropic transmission, is shown schematically in Figure 13-4B. According to the model, the transmitter substance Figure 13-4B. Models of metabotropic synaptic transmission. interacts with the receptor on the Here the second messenger is shown as cAMP, but cGMP or another substance or even several different substances could postsynaptic membrane, activating serve as well. adenylate cyclase and producing cAMP. The cAMP activates a protein than others. For example, the interval kinase, phosphorylating a protein. It is the between the arrival of the presynaptic spike of the protein which at the synapse and the change in membrane produces the change in membrane potential, potential, the synaptic delay, is shorter at either through a change in membrane ionic the neuromuscular junction, where conductance or through stimulation of an acetylcholine is the transmitter substance, electrogenic pump. The process is reversed than at sympathetic postganglionic synapses, by dephosphorylating the protein and where norepinephrine is the transmitter substance. Surprisingly, acetylcholine acts faster at the neuromuscular junction than at 3 A term used here in the sense of a the parasympathetic junctions at the heart. molecule or molecules that bind specifically the transmitter substance.

13-7 hydrolyzing cAMP. Often associated with some sample records. If we stimulate a metabotropic transmission is an increase in peripheral nerve at weak intensity while membrane resistance, not a decrease as in recording from a motoneuron, we see in the ionotropic transmission. record a hypopolarization with a latency of It has also been suggested that the longer 1-2 msec, followed shortly by a latencies and durations of the muscarinic repolarization of the cell. This response is effects of ACh and the effects of dopamine the excitatory , or and norepinephrine may be partly the result EPSP, shown in Figure 13-5B. It has a of having long diffusion distances between the site of release at the presynaptic terminal and the site of action, i.e., that the synapses differ from the classical 15- to 200-nm cleft variety. These have sometimes been called nonsynaptic interactions, but the current trend is to call them loose synapses. Longer synaptic delays can readily accommodate longer diffusion times. Of course, this usage makes transmitter substances subtly merge with neurohormones. Table 13-1 shows that , GABA, L-glutamate, and L-aspartate are probably ionotropic transmitter substances. Norepinephrine, dopamine, , epinephrine, histamine, and probably substance P are metabotropic. Acetylcholine is sometimes ionotropic (at nicotinic cholinergic synapses; those also activated by nicotine), and sometimes metabotropic (at muscarinic cholinergic synapses; those also activated by muscarine). The second messenger at metabotropic (muscarinic) cholinergic synapses is thought to be cyclic guanidine monophosphate (cGMP). Figure 13-5. A. The method of recording the The excitatory postsynaptic potential. postsynaptic potential with a micropipette. B-E. The postsynaptic cell can either EPSPs elicited in a motoneuron by stimuli to a hyperpolarize or hypopolarize in response to peripheral nerve at increasing strengths. Note that the critical firing level is achieved and that the transmitter substance. It is possible to the action potential is initiated in E. (Eccles JC, study the postsynaptic events by puncturing Eccles RM, Lundberg A: J Physiol (Lond) the soma of a cell with a microelectrode to 136:527-546, 1957) pick up the changes in membrane potential that result from activity in a presynaptic axon. The arrangement of the cell and the electrode is shown in Figure 13-5 along with

13-8 decay time-constant of about four msec and, like the generator potential, is a local or nonpropagated event. The EPSP is in fact a generator potential; it is sufficiently important to warrant special consideration and a name of its own. The amplitude of the EPSP varies with the strength of the stimulus (that is, with the number of fibers stimulated), as shown in Figure 13-5C-E, and if it hypopolarizes the membrane to or Figure 13-6. Structure of the neuromuscular beyond its critical firing level, the junction. The terminal of the motoneuron is expanded over the synaptic cleft. M uscle motoneuron will discharge an action membrane is deeply infolded under the terminal. potential (Fig. 13-5E). The neuromuscular junction: an example of excitatory transmission. It is possible to remove the muscle and We can use transmission at the its nerve from an organism and put it into a neuromuscular junction as an example of bath of Ringer's solution (a balanced ionic excitatory transmission because it displays solution, the ionic constituency of which is many of the important features of such similar to that of blood). The nature of such transmission. It is also of historical interest a preparation is shown in Figure 13-7. because it was in the neuromuscular junction When a microelectrode is used to penetrate that most of the early studies of synaptic the muscle, a resting membrane potential transmission were done. It is easily accessible, and the postsynaptic cell (in this case a striated muscle cell) is large and easily penetrated by recording electrodes. The neuromuscular junction or motor end- plate is morphologically much like any other synapse except that it is larger. The axon of the motoneuron loses its myelin sheath near its termination and expands greatly, forming Figure 13-7. Recording setup for the end-plate a bouton that is 10 :m or so in diameter. It potential. Muscle is bathed in Ringer's solution contains synaptic vesicles, known to contain containing curare, and motor axon is placed on the transmitter substance, acetylcholine, in stimulating electrodes. A recording micropipette its terminal. The postsynaptic element in penetrates the muscle membrane at 1-mm intervals away from the end-plate. Sample records this synapse is a skeletal muscle cell whose show the nature of the recording at each site. membrane is specialized at the end-plate by numerous deep infoldings. Only the peaks (Vr) of about -70 mV is recorded as of these folds are near the motoneuron described in Chapter 3. terminal, but the depths of the folds are in contact with the fluid of the synaptic cleft. The structure of the neuromuscular junction is shown in Figure 13-6.

13-9 When the axon of the motoneuron is hypopolarizes the membrane and, when the stimulated, it can be excited to discharge a membrane potential crosses the critical spike that conducts down to the terminal. firing level, an action potential is initiated in Hypopolarization of the terminal by the the muscle membrane. In Figure 13-7, the action potential opens the voltage-gated Ca++ instant when the stimulus is applied to the channels, Ca++ enters the terminal, the nerve is signaled by the stimulus artifact (a synaptic vesicles fuse with the terminal nearly instantaneous spread of stimulus membrane, and acetylcholine is released into current from stimulating to recording the synaptic cleft. The acetylcholine electrodes) and then, after a suitable time for diffuses across the synaptic cleft from conduction along the axon and for synaptic presynaptic to postsynaptic in less than 100 delay, the membrane hypopolarizes, leading :sec and interacts with the acetylcholine to the action potential. receptors on the folded postsynaptic, muscle If the preparation has been bathed in a membrane. The acetylcholine receptor is solution containing the drug curare, a believed to be a pentameric glycoprotein substance used experimentally as a muscle composed of 4 types of transmembrane relaxant and used by South American polypeptides. Two acetylcholine molecules Indians as a poison that is applied to arrowheads, the stimulus to the nerve leads Figure 13-8. The spike to a change in potential, called the end-plate and the end-plate potential. The end-plate potential looks and potential. A. The spike behaves much like EPSPs in nerve cells; an recorded by a transmembrane example is shown in Figure 13-8B for micropipette from the comparison with the uncurarized spike in muscle. B. The end-plate A4. Like the EPSP, the end-plate potential is potential recorded after graded and non-propagated, as shown by the the spike has been decreasing amplitude as the potential is blocked with curare. recorded further from the end plate (reading traces toward the right in Figure 13-7). As bind to the pentamer with weak the electrode is moved farther and farther cooperativity and cause a conformational along the muscle membrane away from the change. The binding of the acetylcholine end-plate, the potential drops in amplitude opens the channel which has an effective because it conducts electrotonically. As in diameter of 0.65 nm, and it is nonselective, other synapses, the receptor region of the i.e., it is permeable to small ions–Ca++, Na+, postsynaptic membrane contains no voltage- K+ and Cl-. Because the channel is gated channels and therefore does not nonselective, the contribution that any ion discharge spikes, but the end-plate potential makes to the total current is a function of its has only to bring the adjacent membrane to driving force and concentration. As a result critical firing level to initiate an action the total ionic current is comprised mainly of potential there. Normally, in the absence of Na+ current because of its large curare, the end-plate potential is more than electrochemical gradient at the resting membrane potential and its high external concentration. Inward Na+ current 4 Recordings in this figure were obtained using the setup in Fig. 13-7.

13-10 large enough to bring the membrane to the course and configuration reminiscent of the critical firing level; an action potential is end-plate potential, and they are termed initiated in the muscle fiber for each spike in miniature endplate potentials or MEPPs. the motoneuron connected to it. Pharmacologically and physiologically, it Acetylcholine acts to open the ionic has been demonstrated that MEPPs have the channels in the postsynaptic membrane for same properties as the end-plate potential only 1-2 msec; the remainder of the end- and that they are caused by spontaneous plate potential is simply due to the passive release of small quantities of acetylcholine. properties of the muscle membrane. After MEPPs tend to have the same amplitude or 1-2 msec, the acetylcholine is removed from multiples of their smallest amplitude, so it is the receptor and hydrolyzed by the enzyme surmised that they are caused by release of , which is found on the nearly equal-sized packets of acetylcholine, postsynaptic membrane mainly in the region called quanta. It seems reasonable to of the synaptic cleft. Acetylcholinesterase is assume that a quantum is the amount of capable of hydrolyzing about 10 transmitter in a single vesicle. It also seems acetylcholine molecules per msec. reasonable that the end-plate potential is Therefore, most of the transmitter substance always composed of integral multiples of a is hydrolyzed, and the products are taken up MEPP. again by the motoneuron terminal, but some of the acetylcholine escapes from the cleft and is carried away by the blood. There is no danger that this escaped transmitter can re-excite the muscle because it is only effective in changing the membrane potential when applied to the membrane within the cleft, i.e., there are no active receptors on the muscle membrane except in the cleft. Within the motoneuron terminals, acetylcholine is stored in the synaptic Figure 13-9. The surface of a motoneuron soma vesicles, each vesicle containing about studded with boutons terminaux. (Schadé JP, 10,000 molecules of acetylcholine. Because Ford DH: Basic Neurology. Amsterdam, Elsevier, the transmitter substance is stored in this 1965) fashion and because the entire content of a vesicle is released or none of it is released, it MEPPs occur spontaneously at irregular is reasonable to assume that the end-plate intervals with a low rate of occurrence at the potentials must be made up of some multiple resting end-plate. The motoneuron spike of the potential change caused by a single increases the rate of occurrence of MEPPs vesicle's contents. Actually, when for a short time, 1-2 msec, during which recordings are made from a nerve-muscle 200-2,000 quanta, depending upon the preparation (Fig. 13-7) at rest, small, particular nerve-muscle preparation, are spontaneous hypopolarizations are seen in released. Each quantum opens up to 2,000 the membrane potential. These have a time- channels and each channel can admit as

13-11 many as 20,000 Na+ ions. The potential for diaphragm. change in the membrane potential of the The disease myasthenia gravis is muscle is enormous and therefore always characterized by muscle weakness after more than enough to cause a spike in repeated activation of the neuromuscular normal, healthy muscle. junction, but not for a single activation. Because the process of transmission at Patients typically are strong in the morning, the neuromuscular junction contains so but become progressively weaker as the day many different steps, the possibilities for goes on. The problem with the myasthenic interference with the process are numerous. appears to be threefold: (1) there is an Curare has already been mentioned as a abnormality of the immune system such that blocker; curare competes with acetylcholine antibodies are formed against the for the receptor sites, but is incapable of acetylcholine receptor, and the number of activating them. Other competitive receptors is reduced; (2) there is a decreased blockers, such as or ability to resynthesize acetylcholine from the succinylcholine, not only compete, but acetate and choline taken up into the activate the receptor. Their paralyzing effect terminals; and (3) there is increased is due to the tenacity with which they bind hydrolysis of acetylcholine. With repeated the receptor and the difficulty with which activation of the synapse, the vesicular they are removed from the receptor and stores of acetylcholine are depleted, not hydrolyzed. replenished as they normally would be, and The toxin of botulinus bacteria, found in after a while the junction fails to transmit. some spoiled food, is an extremely powerful In addition, the reduction in the number of neuromuscular blocker that works by receptors means that less of the preventing the release of the transmitter acetylcholine available can be bound. substance from the motoneuron terminals. Administration of anticholinesterase drugs Low Ca++ concentrations in the extracellular like is sometime effective in fluid also prevent release of transmitter treatment of myasthenia, probably because substance. Elevated Mg++ or Mn++ levels they make the acetylcholine remain in the also block release, but they work by cleft longer, increasing the likelihood that it competition with Ca++. will bind to a receptor and activate the Neuromuscular blocks can also be muscle. created by interfering with the action of the Synaptic transmission between neurons. ACh-degrading enzyme Synaptic transmission between neurons is acetylcholinesterase. basically the same as at the neuromuscular inhibitors, such as neostigmine, block the junctions. Transmitter substance release is removal and hydrolyzation of acetylcholine; triggered by terminal hypopolarization and is thus, the muscle membrane stays dependent upon Ca++. The release process is hypopolarized for too long a period and the quantal in nature, and transmitter release muscle cannot relax. This is the principle of occurs spontaneously. Synaptic action of many insecticides and nerve gases. transmission is terminated by removal of the Prolonged hypopolarizations lead to transmitter substance from the synaptic cleft convulsions, then to paralysis and death, through or hydrolysis. One usually caused by paralysis of the fundamental difference is that in synaptic

13-12 transmission between neurons, an EPSP in encrusted with boutons from afferent fibers the postsynaptic neuron, caused by a single of various sources, to show how extensive spike at a single synapse, seldom is large neural interconnections are. Estimates of the enough to trigger a spike. In general, the density of synapses on motoneurons have EPSPs caused by a single presynaptic action indicated that boutons cover 40-50% of the somatic and 50-80% of the dendritic surfaces. If we stimulate more than one of these afferent fibers with a single stimulus, then each active fiber will release its transmitter substance onto the membrane of the motoneuron and cause its own EPSP, and we see the algebraic sum of them. In Figure 13-10A are illustrated the EPSPs elicited in a motoneuron by two action potentials in two different afferent fibers, when stimulated separately and when stimulated together. The response to simultaneous stimulation is clearly seen to be the algebraic sum of the two single responses. This is an example of spatial summation. Like all generator potentials, EPSPs can show temporal summation. If the same afferent axon is stimulated twice in rapid succession, the response to the first stimulus is not yet over before the response to the second begins. The changes in potential Figure 13-10. Spatial and temporal again sum, but because they do not start at summation of EPSPs. A. EPSPs elicited by stimulation of two fibers afferent to a exactly the same time (2 msec apart), the motoneuron both separately and sum is a bit irregular in shape (Fig. 13-10B). simultaneously. Notice the algebraic This is an example of temporal summation. summation. B. EPSPs elicited by a single The membrane potential can be brought to stimulus to a fiber afferent to a motoneuron and two stimuli applied in firing level by summation, spatial or rapid succession (2 msec apart). temporal or both. Any number of EPSPs, from a variety of types of presynaptic potential are small, only 1-2 mV of neurons, can be summed by a single hypopolarization, and cannot bring the postsynaptic cell. postsynaptic cell to critical firing level. For the postsynaptic cell to be excited to discharge requires spatial and temporal summation, the same two phenomena discussed previously. Figure 13-9 shows a sketch of the soma of a motoneuron, literally

13-13 Synapses inhibition at neuronal synapses. Inhibition is that require a not seen in mammalian neuromuscular lot of junctions. With an appropriate stimulus, the summation to response of the motoneuron can be an reach firing hyperpolarization, beginning 3-4 msec after level are called the stimulus, followed by a return to the integrative resting potential, again with a decay time- synapses, and constant of about four msec. This response they make up is called the inhibitory postsynaptic the bulk of the potential, or IPSP, because it drives the synapses in the membrane 1-4 mV away from the critical nervous firing level and therefore reduces the system. A few frequency or, alternatively, the probability of synapses firing of the postsynaptic cell. Figure 13-11 require only shows that as the stimulus strength increases one (from top to bottom), so does the amplitude presynaptic of the IPSP. Like the EPSP, the IPSP is a action nonpropagated event. IPSPs can sum either potential to spatially or temporally to hyperpolarize the bring the Figure 13-11. An IPSP elicited cell to an even greater extent than a single by a single stimulus applied to postsynaptic a peripheral nerve at IPSP. IPSPs are never seen in mammalian membrane to increasing strengths from top muscles. critical firing to bottom. level, and these are called obligatory synapses. An example of an obligatory synapse is the neuromuscular junction. A single action potential in a single "-motoneuron causes a postsynaptic action potential in every extrafusal muscle fiber in its motor unit (a motoneuron plus all the muscle fibers it innervates is a motor unit). Generation of the action potentials in the "-motoneurons themselves requires considerable summation, and therefore synapses on motoneuron somata or dendrites are integrative. Not all neurons behave exactly like motoneurons, but most use this same basic mechanism for transmission at Figure 13-12. The effectiveness of an IPSP in chemical synaptic junctions with other cells. reducing EPSPs. A. The EPSP by itself. B. The The inhibitory postsynaptic potential. IPSP by itself. C. The EPSP and IPSP initiated at Another difference between neuronal and the same time. D. A much larger EPSP by itself. neuromuscular synapses is the possibility of E. The EPSP in D with the IPSP in B.

13-14 Ionic mechanisms of postsynaptic potentials. It appears that the excitatory transmitter substances responsible for the EPSP act at the postsynaptic membrane by increasing the permeability of the membrane to all small ions, including sodium, potassium, calcium and chloride ions; there is an increase in net flux of ions, with all ions moving down their electrochemical gradients. The major contributor to the change in potential is sodium current because of the large driving force Figure 13-13. Current flow at synapses. (membrane potential minus equilibrium Excitatory and inhibitory synapses are potential) on sodium ions and the large indicated on the soma and proximal dendrites change in sodium conductance. It is also and currents initiated at each, flowing through apparent that the change in the membrane's the postsynaptic membrane and the region of the , where the spike is thought to permeability to sodium is much larger than be initiated. the change for potassium, because the potential that the membrane is seeking , during the EPSP, the equilibrium potential postsynaptic cell, Vr= Cl-, then chloride of the EPSP, is 0 to +30 mV, the exact value current will be zero, and chloride will make depending upon what synapse is being no contribution to the hyperpolarization. If , studied. Recall that the resting membrane's Vr is less negative than Cl-, then the driving permeability to sodium is only 1/30th of that force on chloride will move it inward, to potassium, making the resting potential creating an outward current. Under this very near the potassium equilibrium circumstance, an increase in chloride potential. If the membrane is suddenly made conductance will hyperpolarize the

30 times more permeable to sodium ions, the membrane. On the other hand, if Vr is more , membrane potential will shift to a level negative than Cl-, then the driving force on halfway between the sodium and potassium chloride will move it outward, creating an equilibrium potentials, about -15 mV. In inward current. Under this circumstance, an fact, during the EPSP the membrane increase in chloride conductance will potential shifts farther, to 0 to +30 mV, so actually hypopolarize the cell. Vr is always , the relative change in sodium permeability less negative than K+, so an increase in must make the permeability ratio much potassium conductance always results in greater than 1:30, in fact, greater than 1:1. hyperpolarization. Chloride and potassium Apparently, chloride plays no major role in are nearly in electrochemical equilibrium, this process, but any chloride cur-rent would and therefore their driving forces are small, , tend to hold the membrane near Cl-, i.e., but then the amplitude of the IPSP is also near Vr. small. The IPSP, on the other hand, is produced It is important that the inhibitory effect by increased permeability of the membrane of the IPSP is not due simply to the to chloride or potassium or both. If, in the hyperpolarization, driving the membrane

13-15 to hypopolarize the cell to the same level as the original EPSP, as shown in E. This happens because the IPSP results from an increased membrane conductance for K+ and Cl-. This means that the membrane resistance (R=1/g) is decreased. The inward Na+ current of the EPSP therefore produces a smaller voltage drop across the smaller membrane resistance (V = iR, Figure 13-14. The combination of EPSPs and IPSPs to R is reduced) and a smaller EPSP. The generate different patterns of spike discharge. Inset shows a IPSP inhibits both by virtue of the neuron with three synaptic junctions--two on the soma and decreased membrane resistance and the one on a proximal dendrite. Two of the synapses are excitatory; one is inhibitory. A. Transmembrane potential hyperpolarization. The recorded with the micropipette, with different temporal hyperpolarization forces a greater arrangements of a single postsynaptic potential at each amount of hypopolarization to achieve synapse (indicated by letters under trace). For the purpose of critical firing level, and the decreased illustration, EPSPs and IPSPs are shown larger than normal; membrane resistance reduces the size they can cause the membrane potential to cross the critical firing level (CFL). B. The spike trains that would be recorded of the EPSP. For this reason, inhibition from the axon of the cell as generated by the synaptic always makes itself felt. Equal potential patterns in A. excitatory and inhibitory presynaptic inputs to a cell always result in away from the critical firing level, but also inhibition of its discharge. And it is for this includes another process. If the effect were reason that increasing Cl- conductance simply due to the hyperpolarization, then inhibits even though Cl- is in summation between EPSPs and IPSPs electrochemical equilibrium and changing it would still be linear, IPSPs summing with a conductance produces no voltage change in negative sign. The maximum change in the cell. voltage of the EPSP is 8-10 mV, whereas The postsynaptic membranes at all that for the IPSP is 2-4 mV; yet an IPSP can synapses are electrically inexcitable; the reduce the amplitude of an EPSP by more action potential is initiated somewhere else than its own amplitude, that is, they do not on the membrane. Most people think that sum algebraically. This is shown in Figure the spike in most neurons is initiated in the 13-12. When the appropriate pathways to a region where the axon is connected to the cell are stimulated, an EPSP and an IPSP are soma, the axon hillock. The axon hillock is initiated in the cell, as shown in A and B. If thought to have an electrical threshold about the EPSP and the IPSP are initiated at the half that of the soma and dendrites, so that same time, the resulting change in potential the spike is initiated there first. Figure 13- is a small hyperpolarization as shown in C, 13 shows a drawing of the neuron showing not the small hypopolarization that would be the axon hillock, synaptic junctions on the expected if there were algebraic summation. soma and dendrites, and the currents that An EPSP (D) larger than the IPSP (in terms flow when the synapses are active. EPSPs of amplitude) must be added to the response and IPSPs are not propagated, but spread

13-16 electrotonically into the region of the of discharge in the axon hillock (B). Shown hillock. This means that, for synapses are two excitatory synapses, one on the soma producing equal changes in membrane and one on a dendrite, and one inhibitory potential at the synapse, the ones closer to synapse on the soma. Each pattern in A was the hillock have a greater influence on the generated by some combination of inputs firing of the cell. However, synapses on over the three synapses (indicated by the dendrites tend to generate particularly large letters: a, b and c). The same synapses are EPSPs, somewhat offsetting their greater involved in generating each pattern; only the distance. Inhibitory synapses, synapses that order and timing are changed. Even small produce IPSPs, also tend to be located closer changes result in noticeably different than excitatory synapses to the axon hillock patterns of spike discharges, with great (the spike-generating region). This consequences for behavior. arrangement may also add to the great If the precise timing required to produce influence of IPSPs on the neuron membrane. spatial and temporal summation is altered, The firing pattern of the neuron is the precise firing patterns of completely determined by the sum of its and motoneurons required to produce even synaptic bombardment, both excitatory and the simplest of movements are no longer inhibitory. This is especially important in possible. In fact, the real impact of certain cells with integrative synapses. It was demyelinating diseases such as multiple pointed out in the earlier discussion of sclerosis is not due to destruction of neurons generator potentials that there is a linear or even blockage of conduction; they still relationship between generator potential conduct (at least in the early stages of the amplitude and the frequency of discharge in disease), although at reduced velocities after the receptor or its nerve. The EPSP is a the myelin is removed. The slowed generator potential, and, like any good conduction in a demyelinating disease generator potential, its amplitude is related means that some impulses do not arrive on to discharge frequency in a linear way. The time at synapses on motoneurons. hypopolarization at the axon hillock is Considering the time constant of an EPSP, a increased by summation of EPSPs from slowing of conduction that produces even a different synapses and decreased by 0.5-msec delay in the arrival of an impulse summation of IPSPs. As a result, the firing at the synapse can have devastating effects frequency increases or decreases. Figure 13- on movement. The timing of the arrival of 14 shows a hypothetical arrangement of impulses is also important in sensory events. synapses on a cell and some different Humans use small differences in the time of configurations of synaptic potentials at the arrival of a sound at the two ears to localize axon hillock (A)5 and the resulting patterns the source of sounds with low frequencies. This difference in arrival time can be as little as 30 :sec. Clearly, very close timing of 5 The spikes have been omitted from impulses is essential to this behavior. trace A for clarity. Obviously, they would Rectification6. In the initial discussion be superimposed on top of the traces in an actual recording. Also the postsynaptic potentials are shown larger than normal for 6 Here the term rectification is used in the illustration. engineering sense of a lower resistance to

13-17 of the initiation of an action potential in ganglia by preganglionic neural input, it can axons, it was noted that, with electrical inhibit the release of acetylcholine within stimulation, once the critical firing level is that . reached, the action potential propagates in In some cases, the postsynaptic potential both directions away from the point of elicited by a given transmitter substance can stimulation. The direction normally taken be altered by, or contingent upon, the by action potentials is the orthodromic postsynaptic action of a neuromodulator. direction; the reverse is the antidromic For example, a brief exposure to dopamine direction. If the action potentials can travel released synaptically into sympathetic down an axon both ways, why is there a ganglia enhances the muscarinic "normal" direction? The answer lies in the hypopolarizations induced by acetylcholine synapse. When the action potential reaches for hours, even though the dopamine causes a synapse it can go no further, but it can no change in the membrane potential or cause a release of transmitter substance in a resistance of the postsynaptic cell. Similar presynaptic element. There is usually no effects of dopamine have also been transmitter mechanism in the postsynaptic described in the caudate nucleus and element; therefore, synapses act as rectifiers, . A shorter potentiation of both allowing transmission in only one direction. excitatory and inhibitory responses of Modulatory role of transmitter Purkinje cells in the cerebellar cortex is substances. The term neuromodulator has induced by norepinephrine released by axons been coined to describe certain functions of originating in the locus ceruleus. transmitter substances (or putative It has been suggested that these longer transmitter substances). A transmitter lasting changes in neural activity produced substance acts as a neuromodulator when it by neuromodulators may play a role in alters the synaptic action of other neural slowly developing and enduring behavioral inputs by means other than itself producing changes such as learning and . The direct excitation or inhibition. In other effects of drugs on words, it acts by means other than eliciting learning and monoamines on sleep/waking EPSPs or IPSPs. Neuromodulators can and learning may indicate that this change the release of a transmitter substance suggestion has some credence. from presynaptic terminals. This can be accomplished by way of , Physiology of an electrotonic synapse. which when bound by a transmitter In known examples of electrotonic substance, modulate further release of that synapses in invertebrates, the anatomical substance, or it can occur when one substrate of transmission is a gap junction in transmitter substance modulates the release which the joined membrane is of lower of another. Norepinephrine at some resistance than surrounding membrane, i.e., synapses in the autonomic nervous system the cell-to-cell resistance is less than the can inhibit its further release. When cell-to-extracellular fluid resistance, and it is enkephalin is released into sympathetic electrically inexcitable, i.e., it does not generate action potentials. An impulse propagates into the region of the junction, transmission in one direction than in the and the resulting current flows across the opposite direction.

13-18 frequencies of up to 100/sec and presumably is used by the for guidance or perhaps communication. The recording arrangement is shown in A. Histologically, these motoneurons have been shown to be interconnected by thick dendritic or somatic processes, as shown. The recordings in B-I are made from neurons 1 (marked 1), from neuron 2 (marked 2), and from the current applied to the cells (marked i). An hyperpolarizing current was Figure 13-15. Electrotonic spread between spinal neurons in an electric applied to neuron 1, and fish. A. Recordings are made simultaneously of the membrane potentials responses were recorded of two neurons while either one is hypopolarized or hyperpolarized through an intracellular electrode. B-G. The responses of both cells are from both neurons in Figure shown to hyperpolarization of neuron 1 (B) or neuron 2 (C), 13-15B. Both cells were hypopolarization of neuron 1 below (D) and exceeding its critical firing hyperpolarized. A similar level (F), and hypopolarization of neuron 2 below (E) and exceeding its result occurred when an critical firing level (G). H. An impulse is initiated by a brief stimulus to hyperpolarizing current was neuron 1, and it spreads to neuron 2. I. The same as in H except that neuron 2 is strongly hyperpolarized; this fails to block spread of the applied to neuron 2 (Fig. 13- spike from neuron 1 to neuron 2. (Bennett MVL, Pappas GD, Aljure E et 15C). An hypopolarizing al.: J Neurophysiol 30:180-208, 1967) current, applied to either cell, hypopolarized both or, in junctional membrane, out of the presynaptic some cases, caused both to discharge action cell and into the postsynaptic cell. That potentials (Fig. 13-15D-G). Notice that the current must again flow out of the latency of the discharge was longer in the postsynaptic cell (according to Kirchhoff's cell that did not receive the current injection current law), this time through electrically directly. This is due to the slower rate of excitable membrane, causing an rise of the electrotonic potential farther from hypopolarization, which, if large enough, the current source, causing a delay in can cause the postsynaptic cell to discharge. reaching the critical firing level (Fig. 13- Usually, though, the resulting 15F,G). The sort of reciprocal relationship hypopolarization is small, of the order of 1-2 shown in Figure 13-15 is just what one mV. would expect for such an electrotonic Figure 13-15 shows recordings made synapse. Current flows as easily from intracellularly from two spinal motoneurons neuron 1 to neuron 2 as from neuron 2 to that drive the of the electric neuron 1, i.e., the junction is not rectifying. fish, Gnathonemus. The electric organ emits There are a few examples in invertebrates of electrical impulses of 0.3-msec duration at electrotonic synapses that do rectify. This

13-19 can be the result if the two cells have greatly big advantage. The CNS could easily different membrane resistances, membrane produce small time compensations. areas, or voltage thresholds, the latter being Synaptic delay. Transmission at a the voltage at which the synapse begins to chemical synapse requires mobilization of transmit. synaptic vesicles, , diffusion of a transmitter substance (in some cases over Chemical and electrotonic synapses long distances), reaction of the transmitter compared and contrasted. substance with postsynaptic receptor sites, Inhibition. It should be clear that production of changes in membrane chemical synapses can produce either permeability, and a change in membrane hypopolarizations potential, produced either directly or through (excitation) or hyperpolarizations a second messenger. All of these steps take (inhibition) in the postsynaptic cell. As far time. This time is called the synaptic delay, as we know, axons do not carry propagated and it is measured as the time between hyperpolarizations in any nervous system, arrival of the impulse at the presynaptic and therefore simple hyperpolarizing terminal and the start of the postsynaptic postsynaptic potentials will not occur at response. In mammals, the ionotropic electrical synapses. There is the possibility synaptic delay is of the order of 0.1-0.3 of transmission of hyperpolarizing after- msec. At the neuromuscular junction, most potentials at electrical synapses, especially if of the delay consists of the time required for transmission at the junction were rectified in release of the chemical transmitter the proper direction. If the polarity of substance. Diffusion time and onset of rectification is such that hypopolarizations permeability changes apparently contribute pass more easily from pre- to postsynaptic little to it. and hyperpolarizations from post- to The process of electrical transmission presynaptic, a large hyperpolarizing after- occurs with minimal delay, usually less than potential in the postsynaptic cell would then 0.05 msec. It is this short delay that gives produce a feedback inhibition of the electrical synapses their usefulness as neural presynaptic cell with little feedback synchronizers. The electrical inter- excitation (Table 13-3). Such a possibility connection of neurons causes them to tend to has been suggested for synapses in Aplysia. fire synchronously. This is presumably of The advantages of chemically mediated advantage when rapid movements or high- inhibition are that it can be larger in size, frequency events, such as electric organ i.e., a greater hyperpolarization; longer in discharges, are being controlled. What other duration; and not limited in its site of advantages it may confer on a system are not application. Electrically mediated inhibition known. would occur more rapidly, because of the lack of synaptic delay, but this need not be a

13-20 Table 13-3

Properties of Single Chemical and Electrical Synapses Property Chemical synapses Electrical synapses 1. Rectification Always Sometimes, usually not 2. Amplification Yes No 3. Delay Yes No 4. Inhibition Yes Yes 5. Summation Yes Yes, but over shorter time 6. Influenced by membrane Yes No potential

Rectification. Because of the locations typically last 10 msec or longer, whereas of synaptic vesicles and receptors for those at electrical synapses seldom outlast the transmitter substance at chemical synapses, duration of the presynaptic spike, i.e., about 1 the latter are, of necessity, rectifying msec. Therefore, summation can occur over junctions, i.e., they allow transmission in a period 10 times (or more) longer at only one direction, as we have already chemical synapses. discussed. In cases of reciprocal synapses, Amplification. At chemical synapses, there is a mechanism for removing there can be an effective amplification of the rectification, but it is not known how transmitted signal such that the electrical pervasive this mechanism may be. It does energy of the postsynaptic response is greater exist in the retina and the olfactory bulb. As than that of the presynaptic response. This we have already mentioned, most electrical can occur if the resistance of the postsynaptic synapses appear to be nonrectifying; membrane is higher than that of the however, the study of rectification requires presynaptic membrane or if the change in intracellular recording and stimulation of membrane permeability, brought about by a both the pre- and postsynaptic elements of single presynaptic spike, is extremely large. the synapse, which is seldom possible in This may manifest itself as an increase in the vertebrates. number of action potentials discharged by the Summation. The processes of spatial postsynaptic cell. Amplification has been and temporal summation in chemical observed for neurons in the dorsal horn of the synapses are general integrative properties of spinal cord that are connected to cutaneous neurons and fundamental to operation of the primary afferent neurons (Tapper DN, Mann nervous system. They are also properties of MD: Brain Res 11:688-690, 1968). It electrical synapses. The major difference probably also occurs at the synaptic junctions between summation by chemical and by between receptors and other cells that do not electrical mechanisms is the longer time- generate action potentials themselves and course of chemical summation. The neurons that do generate action potentials, postsynaptic potentials at chemical synapses e.g., bipolar and ganglion cells in the retina.

13-21 EPSPs, these recorded from a frog sympathetic cell, and IPSPs, recorded from a cat motoneuron, is shown in Figure 13-16. In Figure 13-16, A8 and B4 show the normal configurations of the EPSP and IPSP, when initiated with the cell at resting membrane potential. If the cell is hypopolarized, the IPSP gets larger (Fig. 13-16, B4-1) because the driving forces get larger as the membrane potential gets further removed from the equilibrium potentials of the ions whose permeability is changed, i.e., chloride and potassium. The EPSP, on the other hand, gets smaller as the membrane is hypopolarized (Fig. 13-16, A8-6), until it disappears at about -10 mV (Fig. 13-16, A5) and is replaced by a negative-going potential Figure 13-16. Demonstration of the (Fig. 13-16, A4). The value of the membrane equilibrium potentials of the EPSP and IPSP. A. The influence of changes in potential at which the EPSP disappears is membrane potential (indicated at the end of called the equilibrium potential for the each trace), induced by passing current , EPSP, EPSP, and it is determined by the through an intracellular electrode, on the equilibrium potentials for the ions whose EPSP recorded from a frog sympathetic gangion cell is shown. The resting potential conductances change during the EPSP, i.e., + + for this cell was -80 mV, and the primarily Na and K , with a weighting factor equilibrium potential for the EPSP (A5) was related to the amount of conductance change, -10 mV. (Nishi S, Koketsu K: J Cell Comp as indicated in equation 5 of Chapter 3. If the Physiol 55:15-30, 1960) B. The influence of permeabilities for both Na+ and K+ change, membrane potential on the IPSP recorded from a motoneuron in the cat. The resting then the equilibrium potential for the EPSP is membrane potential for this cell was -74 somewhere between the sodium equilibrium , mV, and the equilibrium potential for the potential, Na+, and the potassium IPSP was -81 mV (not shown). (Coombs JS, , equilibrium potential, K+. The squid giant Eccles JC, Fatt P: J Physiol (Lond) synapse has a of +20 mV, 130:326-373, 1955) the cat motoneuron, 0 mV, and the No such amplification has ever been seen in neuromuscular junction, -15 mV, indicating an electrical synapse. that different relative permeability changes Influence of membrane potential. for Na+ and K+ ions occur at different Because the postsynaptic potentials at synapses. The relative change in potassium chemical synapses result from changes in conductance is larger for the neuromuscular permeability of the postsynaptic membrane junction than for either the cat motoneuron or to sodium, potassium, chloride, or other . With further ions, their amplitude and polarity are greatly hypopolarization, a new driving force affected by the polarity and magnitude of the develops, but this time in the opposite membrane potential. An example of the direction, moving the membrane back toward , influence of membrane potential upon both EPSP (Fig. 13-16, A4-1).

13-22 One can see that the IPSP decreases in concomitant change in membrane amplitude and reverses (in this case, at about permeability, although an EPSP may lead to a -81 mV) to a hypopolarizing potential as the permeability change in adjacent, electrically membrane is hyperpolarized (Fig. 13-16, excitable membrane. Because the electrical B4-7), whereas the EPSP gets larger (Fig. EPSP is a simple ohmic voltage change (iR 13-16, A5-7). The IPSP gets smaller either drop), it is not influenced by membrane

because iCl- and iK+ exactly balance each potential, and therefore it has nearly the same other (if both ions are involved) or because size at any membrane potential. This is , ix = Vm - x = 0 (if only one ion, x, is shown in Figure 13-15, H and I. (Of course, involved). At the equilibrium potential for if the cell is near critical firing level, the the IPSP, the amplitude of the IPSP is zero EPSP may have a disproportionate effect, i.e., because there is no net membrane current. the cell may discharge.) As the equilibrium potential is exceeded (Fig. 13-16, B5-7), a net current (two ions) Presynaptic inhibition. or new driving force (one ion) develops, but Inhibition of impulse discharge mediated it is in the opposite direction, so the polarity by IPSPs is called postsynaptic inhibition, of the IPSP reverses. The EPSP gets larger because the effect is exerted directly on the with membrane hyperpolarization, primarily postsynaptic cell. Postsynaptic inhibition because the driving force on Na+ increases reduces the cell's excitability to all synaptic as the membrane potential moves further inputs. Another mechanism for producing from the equilibrium potential of the EPSP. inhibition, called presynaptic inhibition, involves effects exerted on a presynaptic . To illustrate this inhibition, let us examine the primary afferent fibers of group Ia. These enter the spinal cord and go, among other places, to the ventral (anterior) horn, where they make synaptic contacts on motoneurons that innervate the muscle from which the afferent fibers originated. (This, as we shall see in Chapter 15, is the anatomical basis of the monosynaptic, tendon tap reflex.) On the boutons of the Ia afferent fibers there are synapses, i.e., synaptic terminals on synaptic terminals. The presynaptic terminals Figure 13-17. The anatomic arrangement of an on the group Ia terminals come from axoaxonic synapse showing the pre- and postsynaptic axons. Also shown is the axosomatic interneurons that are driven by group Ia synapse of a group Ia afferent fiber on the afferent fibers from another muscle. This motoneuron. (Eccles JC: The Understanding of the arrangement is shown in Figure 13-17. The Brain. New York, McGraw-Hill, 1973) synapse between the two axons, the axoaxonic synapse, is excitatory in that the The postsynaptic potential at an presynaptic (interneuronal, in this case) electrical synapse is due to a flow of current action potential produces an EPSP in the through the membrane resistance with no terminal of the group Ia afferent fiber.

13-23 from a more positive level of membrane potential and partly because the hypopolarization (previous to the spike) increased the K+ conductance and partially inactivated the + Figure 13-18. Effect of membrane polarization level on the action potential. B. Na conductance Action potential initiated with membrane at resting potential. A. Spike (accommodation) in the configuration when cell was previously hyperpolarized by 10 mV. When spike membrane. The is initiated in a hypopolarized membrane, the spike is reduced in amplitude. increased K+ Examples are shown for 10 mV (C) and 20 mV (D) hypopolarization. + Horizontal line through each record indicates the current passed through the conductance and Na membrane to change membrane potential before spike was initiated; values on conductance right ordinate. Membrane potential is indicated on left ordinate. (Eccles JC: inactivation reduced the The Physiology of Nerve Cells. Baltimore, Johns Hopkins Press, 1968) ratio of conductances and therefore the If the group Ia afferent fiber terminal positive overshoot potential as predictable membrane is maintained in a slightly from equation 5 of Chapter 3. The spike is, hypopolarized condition and then stimulated therefore, smaller both because it starts closer to initiate an action potential, the action potential will be smaller than one that is initiated when the membrane is at its resting potential, Vr. This result is illustrated in Figure 13-187. Trace B shows the action potential initiated at Vr = -65 mV. The smaller spikes in C and D were obtained when the membrane started at hypopolarized values, Vm = -55 mV and -50 mV. The trace in A shows a larger than normal spike initiated when Vm = -70 mV, i.e., the membrane was hyperpolarized. (Actually, Figure 13-19. A collateral inhibitory circuit. Spike these records were made in a motoneuron, initiated in neuron A invades the collateral to excite the inhibitory that produces but the same thing would presumably IPSPs in neuron B. happen in the axon terminal.) The spike in C and D is reduced partly because it arises to zero and because it does not overshoot as far. This phenomenon is the basis for the 7 The horizontal line through each spike presynaptic inhibitory action. Activity at the indicates the amount of current passed axoaxonic synapse partially hypopolarizes the through the membrane to change the terminal so that, when an action potential membrane potential before the spike was comes down the Ia afferent fiber into that initiated. Calibrate against the right terminal, its amplitude is reduced. Because ordinate.

13-24 the amount of transmitter substance released the motoneuron, this means that transmission by a bouton is proportional to the amplitude through group Ia afferent fibers is reduced, of the action potential in it, less transmitter but transmission through polysynaptic and substance is released, resulting in a smaller supraspinal pathways is still possible. EPSP and less excitation of the postsynaptic All types of primary afferent fibers cell, in this case the motoneuron. Some receive presynaptic inhibition from one measurements indicate that a 15-mV source or another. The terminals of reduction in the amplitude of the presynaptic pyramidal tract fibers in the brain stem have spike will reduce the amount of transmitter been shown to be hypopolarized in the same substance released to 1/10 of its original value. It is usually said that presynaptic inhibition has no direct effect on the postsynaptic cell, but this is not entirely true. The EPSP initiated in the Ia bouton causes the release of a small amount of transmitter substance that raises the level of excitability of the motoneuron slightly. It is possible that this slight increase in excitability may offset a small amount of the decrease in transmitter output caused by the spike in the group Ia afferent fiber. In any case, the Figure 13-20. Circuit for Renshaw inhibition. Spike increased excitability of the motoneuron will (A) generated in the axon at the top of the figure add to the excitatory synaptic activity from invades the axon collateral, exciting the Renshaw other uninhibited boutons on the same cell. cell. The discharges a train of spikes This could give the nervous system a rather (B) in response to a single presynaptic spike (an example of synaptic amplification). The train of subtle way of modulating excitability in spikes in the Renshaw cell produces summed IPSPs certain pathways, a possible function of this in the motoneuron (C). (Eccles JC: The Physiology "presynaptic inhibitory circuit" that has of Nerve Cells. Baltimore, Johns Hopkins press, received little attention. 1968) Pre- and postsynaptic inhibition not only differ in their mechanisms but also in their manner. The significance of the latter effect consequences for the system. With is unknown. Presynaptic inhibition may be postsynaptic inhibition, the postsynaptic cell found to be more wide-spread as information is silenced or at least reduced in its excita- accumulates in the future. Postsynaptic bility to all inputs no matter what their inhibition has been found in every structure source. The consequence for the muscle is of the central nervous system, and our ideas that it relaxes because there is no alternate of its importance and ubiquity seem to be pathway to it. With presynaptic inhibition, increasing. The function of presynaptic the excitation of the postsynaptic cell (in this inhibition on primary afferent neurons may case, the "-motoneuron) through one be to modulate sensory inputs to the spinal synapse is reduced, but all other synapses cord at the earliest possible point, before they perform normally or perhaps even can influence spinal cord activity. In this supranormally (see previous paragraph). For way, the central nervous system can eliminate

13-25 unwanted sensory information. By reducing "-motoneurons, whose axons innervate some sensory inputs, presynaptic inhibition skeletal muscles. The Renshaw circuit is may be useful in certain kinds of contrast shown in Figure 13-20. The axon collateral enhancement. that activates the inhibitory interneuron is short, remaining within the ventral horn of Collateral or recurrent inhibition the spinal cord and releasing acetylcholine at A special case of postsynaptic inhibition its terminal. (Acetylcholine is also released is recurrent inhibition, the circuit for at the muscle.) The inhibitory interneuron, which is shown in Figure 13-19. The output called a Renshaw cell in honor of its of a neuron, neuron A, conducts along its discoverer Birdsey Renshaw, discharges a axon and out one axon collateral to excite an burst of spikes (B) in response to a single interneuron that inhibits another neuron of motoneuron spike (A), releasing a transmitter the same type as neuron A, in this case substance, perhaps glycine, at terminals on neuron B. Many people draw this circuit other "-motoneurons. This leads to a large, showing that the inhibitory interneuron summed IPSP in these motoneurons (C). inhibits neuron A, making neuron A inhibit Again, there is no evidence that an "- itself. Although this is possible, there is no motoneuron inhibits itself through Renshaw evidence that it occurs. The evidence does inhibition. It has been speculated that suggest that neurons inhibit other neurons of Renshaw inhibition may serve to limit the same type. Thus, neuron A inhibits motoneuron firing rates. It is unlikely that neuron B and, similarly, neuron B inhibits this is an important control mechanism for neuron A. Thus, the inhibition may more normal motor activity; motoneurons do not appropriately be termed collateral inhi- discharge at high rates anyway and, at least bition. This is a type of feedback during walking, this kind of inhibition is inhibition, in which the output of a neuron suppressed. It is possible, however, that this is used to inhibit at an earlier point in the kind of inhibition may play an important role pathway. in preventing or limiting certain kinds of Collateral inhibition has been found in pathological or seizure discharges. What else the spinal cord and in nearly every major it might be doing for an organism is not nucleus in the central nervous system, known. notably in the cuneate and gracile nuclei, thalamic nuclei, cerebellar nuclei, cerebellar Summary. cortex, and cerebral cortex. One theory Synapses are functional connections suggests that collateral inhibition in the between cells. Transmission from one cell to thalamus may play a role in synchronizing another at most electrical synapses is just like thalamic activity to produce the cortical transmission along the membrane of one of alpha rhythm (see Chapter 20). It is not the cells. Transmission at a chemical synapse known whether this theory can stand involves release of a transmitter substance empirical tests nor what this kind of from the presynaptic element by inhibition might be doing elsewhere. hypopolarizing its membrane (usually by an A special case of collateral inhibition is action potential). The transmitter substance Renshaw inhibition. This form of can cause an increase in the permeability of inhibition involves the same circuit as in the postsynaptic membrane to small ions, Figure 13-19, in which neurons A and B are resulting in an EPSP, that is an

13-26 hypopolarizing potential with a decay time synaptic delay, and they are not influenced by constant of about four msec and an changing the membrane potential of the amplitude of 1-10 mV. The transmitter postsynaptic cell. Recurrent or collateral substance (a different substance usually) can inhibition involves the use of the output of a also cause an increase in permeability to neuron to inhibit, through an interneuron, chloride and to potassium ions, resulting in other neurons of the same type. Renshaw an IPSP that is an hyperpolarizing potential inhibition is a special case of recurrent with a decay time constant of about four inhibition involving the output of " msec and an amplitude of 1-4 mV. motoneurons and inhibition by Renshaw Neuromodulators are transmitter substances cells. which can alter the effectiveness of other transmitter substances in changing the Suggested Reading: membrane potential of a cell, without 1. Bennett MVL: Similarities between themselves producing any EPSP or IPSP in chemically and electrically mediated the cell. EPSPs drive the membrane transmission. In Carlson FD [ed]: potential toward the critical firing level, Physiological and Biochemical Aspects exciting, and IPSPs drive the membrane of Nervous Integration. Englewood potential away from the firing level, Cliffs NJ, Prentice-Hall, 1968. inhibiting. Postsynaptic potentials exhibit 2. Curtis DR, Johnston GAR: Amino acid spatial and temporal summation. EPSPs do transmitters in the mammalian central not add algebraically to IPSPs, because the nervous system. Ergebn Physiol 69:97- IPSP's increase in conductance reduces the 188, 1974. hypopolarization produced by the EPSP's 3. Horcholle-Bossavit G: Transmission ionic current; the IPSP normally electrotonique dans le systeme nerveux predominates. Inhibition by IPSPs is central des mammiferes. J Physiol postsynaptic inhibition. Presynaptic (Paris) 74:349-363, 1978. inhibition involves an hypopolarization of 4. Krnjevic' K: Chemical nature of synaptic the presynaptic element at a synapse, transmission in vertebrates. Physiol Rev reducing the spike amplitude in it and thus 54:418-540, 1974. the amount of transmitter released by the 5. Libet B: Nonclassical synaptic functions spike. Presynaptic inhibition reduces of transmitters. Fed Proceed 45:2678- transmission through one pathway afferent 2686. to a cell, but not alternative pathways. 6. McGeer RL, Eccles JC, McGeer EG: Postsynaptic inhibition reduces the Molecular Neurobiology of the excitability of the cell itself and thus the Mammalian Brain. New York, Plenum effectiveness of all pathways afferent to the Press, 1978. cell. Both chemical and electrical synapses 7. Pappas GD, Waxman SG: Synaptic fine are capable of rectification, inhibition, and structure-morphological correlates of summation. Chemical synapses are capable chemical and electrical transmission. In of amplification, they have a finite synaptic Pappas GD, Purpura DP [ed]: Structure delay, and they are influenced by changes in and Function of Synapses. New York, postsynaptic membrane potential. Electrical Raven Press, 1972. synapses have not been observed to amplify 8. Schmidt RF: Presynaptic inhibition in input signals. They have essentially no the vertebrate central nervous system.

13-27 Ergebn Physiol 63:19-101, 1971. 9. Tapper DN, Mann MD: Single presynaptic impulse evokes postsynaptic discharge. Brain Res 11:688-690, 1968.

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