Biopsychology, Global Edition, 11th Ed - Neural Conduction and Synaptic Transmission PDF

Chapter 4 Neural Conduction and Synaptic Transmission How Neurons Send and Receive Signals KTSDESIGN/SCIENCE PHOTO LIBRARY Chapter Overview and Learning Objectives Resting Membrane...

Chapter 4 Neural Conduction and Synaptic Transmission How Neurons Send and Receive Signals KTSDESIGN/SCIENCE PHOTO LIBRARY Chapter Overview and Learning Objectives Resting Membrane LO 4.1 Describe how the membrane potential is recorded. Potential LO 4.2 Describe the resting membrane potential and its ionic basis, and describe the three factors that influence the distribution of Na+ and K+ ions across the neural membrane. Generation, Conduction, LO 4.3 Describe the types of postsynaptic potentials and how they are and Integration of conducted. Postsynaptic Potentials LO 4.4 Describe how postsynaptic potentials summate and how action potentials are generated. Conduction of Action LO 4.5 Explain the ionic basis of an action potential. Potentials LO 4.6 Explain how the refractory period is responsible for two ­important characteristics of neural activity. 97 M04_PINE1933_11_GE_C04.indd 97 22/01/2021 10:47  98 Chapter 4 LO 4.7 Describe how action potentials are conducted along axons—both myelinated and unmyelinated. LO 4.8 Explain the shortcomings of the Hodgkin-Huxley model when applied to neurons in the mammalian brain. Synaptic Transmission: LO 4.9 Describe the structure of different types of synapses. From Electrical Signals LO 4.10 Describe how neurotransmitter molecules are synthesized and to Chemical Signals packaged in vesicles. LO 4.11 Explain the process of neurotransmitter exocytosis. LO 4.12 Describe the differences between ionotropic and metabotropic receptors. LO 4.13 Explain how neurotransmitters are removed from a synapse. LO 4.14 Describe the roles of glia and gap junctions in synaptic transmission. Neurotransmitters LO 4.15 Name the major classes of neurotransmitters. LO 4.16 Identify the class, and discuss at least one function of each of the neurotransmitters discussed in this section. Pharmacology of Synaptic LO 4.17 Provide a general overview of how drugs influence synaptic Transmission and Behavior transmission. LO 4.18 Describe three examples of how drugs have been used to ­influence neurotransmission. The other symptoms of Parkinson’s disease are not quite The Lizard: A Case of P ­ arkinson’s so benign. They can change a vigorous man into a lizard. Disease* These include rigid muscles, a marked poverty of sponta- neous movements, difficulty in starting to move, and slow- “I have become a lizard,” he began. “A great lizard frozen in a ness in executing voluntary movements once they have been dark, cold, strange world.” initiated. His name was Roberto Garcia d’Orta. He was a tall thin man The term reptilian stare is often used to describe the char- in his sixties, but like most patients with Parkinson’s disease, he acteristic lack of blinking and the widely opened eyes gazing out appeared to be much older than his actual age. Not many years of a motionless face, a set of features that seems more reptilian before, he had been an active, vigorous businessman. Then it than human. Truly a lizard in the eyes of the world. happened—not all at once, not suddenly, but slowly, subtly, What was happening in Mr. d’Orta’s brain? A group of insidiously. Now he turned like a piece of granite, walked in slow neurons called the substantia nigra (black substance) were shuffling steps, and spoke in a monotonous whisper. unaccountably dying. These neurons make a particular chemi- What had been his first symptom? cal called dopamine, which they deliver to another part of the A tremor. brain, known as the striatum. As the cells of the substantia nigra Had his tremor been disabling? die, the amount of dopamine they can deliver to the cells in the “No,” he said. “My hands shake worse when they are doing striatum goes down. The striatum helps control movement, and nothing at all”—a symptom called tremor-at-rest. to do that normally, it needs dopamine. *Based on Newton’s Madness by Harold Klawans (Harper & Row, 1990). Reprinted by permission of Jet Literary Associates, Inc. M04_PINE1933_11_GE_C04.indd 98 22/01/2021 10:47  Neural Conduction and Synaptic Transmission 99 Although dopamine levels are low in Parkinson’s disease, the tip of another electrode outside the neuron in the extra- dopamine is not an effective treatment because it does not cellular fluid. Although the size of the extracellular elec- readily penetrate the blood−brain barrier. However, knowl- trode is not critical, the tip of the intracellular electrode edge of dopaminergic transmission has led to the develop- must be fine enough to pierce the neural membrane with- ment of an effective treatment: l-dopa, the chemical precursor out damaging it. The intracellular electrodes are called of dopamine, which readily penetrates the blood−brain bar- ­microelectrodes; their tips are less than one-thousandth rier and is converted to dopamine once inside the brain. of a millimeter in diameter—much too small to be seen by Mr. d’Orta’s neurologist prescribed l-dopa, and it worked. the naked eye. He still had a bit of tremor, but his voice became stronger, When both electrode tips are in the extracellular fluid, his feet no longer shuffled, his reptilian stare faded away, the voltage difference between them is zero. However, and he was once again able to perform with ease many when the tip of the intracellular electrode is inserted into of the activities of daily life (e.g., eating, bathing, writing, a neuron that is at rest (not receiving signals from other speaking, and even having sex with his wife). Mr. d’Orta cells), a steady potential of about −70 millivolts (mV) is had been destined to spend the rest of his life trapped inside recorded. This indicates that the potential inside the rest- a body that was becoming increasingly difficult to control, ing neuron is about 70 mV less than that outside the neu- but his life sentence was repealed—at least temporarily. ron. This steady membrane potential of about −70 mV is Mr. d’Orta’s story does not end here. For the pur- called the neuron’s resting potential. In its resting state, poses of this chapter, his case illustrates why knowledge with the −70 mV charge built up across its membrane, a of the fundamentals of neural conduction and ­synaptic neuron is said to be polarized (it has a membrane potential ­transmission is a must for any biopsychologist (see that is not zero). ­Südhof, 2017). This chapter is about neural communication: How sig- nals are sent from cell to cell, within networks of cells. This Ionic Basis of the Resting Potential is not unlike what happens in a social network: Twitter is LO 4.2 Describe the resting membrane potential and an illustrative example. its ionic basis, and describe the three factors When a person in a social network tweets a message, that influence the distribution of Na+ and K+ that message is carried to other people. If the message isn’t ions across the neural membrane. compelling enough, it gets lost in the void. If it is compel- ling, then some will retweet the message, propagating it Like all salts in solution, the salts in neural tissue separate to more people in their own social networks, and so on. into positively and negatively charged particles called ions. Likewise, when a cell in our brain sends a message to the There are many different kinds of ions in neurons, but this cells in its network, if the message is strong enough, some discussion focuses on only two of them: sodium ions and of those cells will propagate the message to other cells in potassium ions. The abbreviations for sodium ions (Na+) their networks, and so on. Conversely, if the message isn’t and potassium ions (K+) are derived from their Latin names: strong enough, the message will be lost. natrium (Na) and kalium (K). The plus signs indicate that each Na+ and K+ ion carries a single positive charge. In resting neurons, there are more Na+ ions outside Resting Membrane the cell than inside and more K+ ions inside than out- side. These unequal distributions of Na+ and K+ ions are Potential maintained even though there are specialized pores in the neural membrane, called ion channels. Each type of In order to understand how a message is conducted within ion channel is specialized for the passage of particular neurons or transmitted from one neuron to another, you ions (e.g., Na+ or K+). For example, some ion channels have to first learn about the membrane potential: the are specialized for the passage of Na + ions, K+ ions, or ­difference in electrical charge between the inside and the other ions. outside of a cell. There is substantial pressure on Na+ ions to enter the resting neurons. This pressure is of two types. First is the Recording the Membrane Potential electrostatic pressure from the resting membrane potential: Because opposite charges attract, the positively charged LO 4.1 Describe how the membrane potential is Na+ ions are attracted to the −70 mV charge inside rest- recorded. ing neurons. Second is the pressure from random motion for To record a neuron’s membrane potential, it is necessary Na+ ions to move down their concentration gradient. Let us to position the tip of one electrode inside the neuron and explain. Like all ions in solution, the ions in neural tissue M04_PINE1933_11_GE_C04.indd 99 22/01/2021 10:47  100 Chapter 4 In the 1950s, Alan Hodgkin and Andrew Huxley Figure 4.1 Three factors that influence the distribution of + + Na and K ions across neural membranes, illustrated in a became interested in the stability of the resting membrane resting neuron. potential. Some Na+ ions do manage to enter resting neu- rons despite the closed sodium channels and some K+ ions 1 Ions in motion move down their concentration do exit; then why does the resting membrane potential stay gradients, thus Na1 will tend to enter K1 fixed? In a series of clever experiments, for which they were and K1 will tend to exit. K1 1 K1 1 Na K awarded Nobel Prizes, Hodgkin and Huxley discovered the answer. At the same rate that Na+ ions leaked into resting K1 K1 K1 K1 K1 neurons, other Na+ ions were actively transported out; and Na1 K1 at the same rate that K+ ions leaked out of resting neurons, other K+ ions were actively transported in. Such ion trans- K1 Na1 Na1 port is performed by mechanisms in the cell membrane Na1 K+ that continually exchange three Na+ ions inside the neuron 2 The negative internal Na1 Na1 for two K+ ions outside. These transporters are commonly charge creates pressure Na1 for both Na1 and K1 to Na 1 referred to as sodium–potassium pumps. enter. Na1 Since the discovery of sodium−potassium pumps, Na1 K1 several other classes of transporters (mechanisms in the Na1 Na1 membrane of a cell that actively transport ions or mol- K1 K1 ecules across the membrane) have been discovered (see Na1 Kaila et al., 2014). You will encounter more of them later K1 K1 Na1 in this chapter. Ex tra K1 Figure 4.1 summarizes the status of Na+ and K+ ions in ce Na1 K1 K1 Cy llu K1 to a resting neuron. Now that you understand the basic prop- la K1 pl r fl as erties of resting neurons, you are prepared to consider how ui K1 m d K1 neurons respond to input signals. Na1 K1 K1 Na1 Na1 Na1 Sodium– Na1 Na1 potassium pump Generation, Conduction, Na1 Na1 Na1 K1 and Integration of 3 Sodium–potassium pumps transport 3 Na1 out for every 2 K1 they transport in. Postsynaptic Potentials What happens when a resting membrane potential is dis- turbed? Typically, disturbances of the membrane potential occur as a result of input from cells that synapse on a neu- are in constant random motion, and particles in random ron. For that reason, such disturbances of the resting mem- motion tend to become evenly distributed because they are brane potential are termed postsynaptic potentials (PSPs). more likely to move down their concentration gradients than In this module, you will learn how PSPs are generated by up them; that is, they are more likely to move from areas of input to a neuron, how they are subsequently conducted high concentration to areas of low concentration than vice to different parts of a neuron, and how they can cause a versa. Likewise, a drop of red ink placed in a bathtub full neuron to fire (produce an action potential). of water will move outwards to areas where there is no ink, and the water will gradually turn pink. So, why then do Na+ ions under electrostatic pressure Generation and Conduction and pressure from random movement not come rushing of Postsynaptic Potentials into neurons, thus reducing the resting membrane poten- tial? The answer is simple: The sodium ion channels in LO 4.3 Describe the types of postsynaptic potentials resting neurons are closed, thus greatly reducing the flow and how they are conducted. of Na+ ions into the neuron. In contrast, the potassium When neurons fire, they release from their terminal but- ion channels are open in resting neurons, but only a few tons chemicals called neurotransmitters, which diffuse across K+ ions exit because the electrostatic pressure that results the synaptic clefts and interact with specialized receptor from the negative resting membrane potential largely holds molecules on the receptive membranes of the next neu- them inside. ron in the circuit. When neurotransmitter molecules bind M04_PINE1933_11_GE_C04.indd 100 22/01/2021 10:47  Neural Conduction and Synaptic Transmission 101 to postsynaptic receptors, they typically have one of two The graded EPSPs and IPSPs created by the action of effects, depending on the neurotransmitter, receptor, and neurotransmitters at particular receptive sites on a neuron’s postsynaptic neuron in question. They may depolarize membrane are conducted instantly and decrementally to the receptive membrane (decrease the resting membrane the axon initial segment. If the sum of the depolarizations potential, from −70 to −67 mV, for example), or they may and hyperpolarizations reaching the axon initial segment ­hyperpolarize it (increase the resting membrane potential, at any time is sufficient to depolarize the membrane to a from −70 to −72 mV, for example). level referred to as its threshold of excitation—usually Postsynaptic depolarizations are called excitatory about −65 mV—an action potential is generated. The action ­postsynaptic potentials (EPSPs) because, as you will soon potential (AP) is a massive but momentary—lasting for learn, they increase the likelihood that the neuron will 1 ­millisecond—reversal of the membrane potential from fire. ­Postsynaptic hyperpolarizations are called inhibitory about −70 to about +50 mV. Unlike PSPs, APs are not graded ­postsynaptic potentials (IPSPs) because they decrease the responses: Their magnitude is not related in any way to the likelihood that the neuron will fire. intensity of the stimuli that elicit them. To the contrary, All PSPs, both EPSPs and IPSPs, are graded potentials. they are ­all-or-none responses; that is, they either occur to This means that the amplitudes of PSPs are proportional to their full extent or do not occur at all. See Figure 4.2 for an the intensity of the signals that elicit them: Weak signals elicit small PSPs, and strong signals elicit large ones. Figure 4.2 An EPSP, an IPSP, and an EPSP followed EPSPs and IPSPs travel passively from their sites of by an AP. generation at synapses, usually on the dendrites or cell body, in much the same way that electrical signals travel Membrane Potential 265 through a cable. Accordingly, the transmission of PSPs An EPSP (millivolts) has two important characteristics. First, it is rapid—so rapid that it can be assumed to be instantaneous for most 270 purposes. It is important not to confuse the duration of PSPs with their rate of transmission; although the dura- Time (milliseconds) tion of PSPs varies considerably, all PSPs, whether brief STIMULUS or enduring, are transmitted almost instantaneously. Second, the transmission of PSPs is decremental: They decrease in amplitude as they travel through the neuron, Membrane Potential 265 just as a ripple on a pond gradually disappears as it travels An IPSP outward. Most PSPs do not travel more than a couple of (millivolts) millimeters from their site of generation before they fade 270 out completely. Time (milliseconds) Integration of Postsynaptic STIMULUS Potentials and Generation of Action Potentials 160 150 An EPSP and Membrane Potential (millivolts) LO 4.4 Describe how postsynaptic potentials summate 140 an AP and how action potentials are generated. 130 120 The PSPs created at a single synapse typically have little 110 effect on the firing of the postsynaptic neuron. The recep- 0 210 tive areas of most neurons are covered with thousands 220 of synapses, and whether a neuron fires is determined by 230 AP the net effect of their activity. More specifically, whether a 240 250 EPSP ­neuron fires depends on the balance between the excitatory 260 and inhibitory signals reaching its axon. It was once believed 270 280 that action potentials were generated at the axon hillock 290 (the conical structure at the junction between the cell body and the axon), but they are actually generated in the adja- Time (milliseconds) cent ­section of the axon, called the axon initial ­segment STIMULUS (see Kuba, Adachi, & Ohmori, 2014; Tian et al., 2014). M04_PINE1933_11_GE_C04.indd 101 22/01/2021 10:47  102 Chapter 4 illustration of an EPSP, an IPSP, and an AP. Although many sum to form a greater signal. The reason that successive neurons display APs of the type illustrated in Figure 4.2, stimulations of a neuron can add together over time is that others do not—for example, some neurons display APs that the PSPs they produce often outlast them. Thus, if a par- have a longer duration, have a lower amplitude, or involve ticular synapse is activated and then activated again before multiple spikes. the original PSP has completely dissipated, the effect of the In effect, each neuron adds together all the graded excit- second stimulation will be superimposed on the lingering atory and inhibitory PSPs reaching its axon initial segment PSP produced by the first. Accordingly, it is possible for a and decides to fire or not to fire on the basis of their sum. brief subthreshold excitatory stimulus to fire a neuron if it The summation of PSPs occurs in two ways: over space and is administered twice in rapid succession. In the same way, over time. an inhibitory synapse activated twice in rapid succession Figure 4.3 shows the three possible combinations of can produce a greater IPSP than that produced by a single spatial summation. It shows how local EPSPs that are pro- stimulation. duced simultaneously on different parts of the receptive PSPs continuously summate over both time and space membrane sum to form a greater EPSP, how simultaneous as a neuron is continually bombarded with stimuli from IPSPs sum to form a greater IPSP, and how simultaneous ­thousands of synapses. Although schematic diagrams of EPSPs and IPSPs sum to cancel each other out. ­neural circuitry rarely show neurons with more than a Figure 4.4 illustrates temporal summation. It shows few representative synaptic contacts, most neurons have how PSPs produced in rapid succession at the same synapse thousands of synaptic contacts covering their dendrites and cell body. To better understand the summation of PSPs, consider what happens to the many ripples on the surface of a pond: The ripples are contin- Figure 4.3 The three possible combinations of spatial summation. uously interacting with each other to generate larger or smaller ripples. The location of a synapse on a neuron’s B C membrane had long been assumed to be an important factor in determining its potential to Excitatory synapses influence the neuron’s firing. Because PSPs are transmitted decrementally, synapses near the axon had been assumed to have the most influ- A ence on the firing of the neuron. However, it has Inhibitory synapses been demonstrated that some neurons have a mechanism for amplifying dendritic signals that originate far from their axon (see Adrian et al., 2014; Araya, 2014). To recording instrument In some ways, the firing of a neuron is like D the firing of a gun. Both reactions are triggered Two simultaneous EPSPs sum to produce a greater EPSP by graded responses. As a trigger is squeezed, A Stimulated B Stimulated A 1 B Stimulated it gradually moves back until it causes the gun 265 265 265 to fire; as a neuron is stimulated, it becomes less polarized until the threshold of excitation is 270 270 270 Membrane potential (millivolts) reached and firing occurs. Furthermore, the firing of a gun and neural firing are both all-or-none Two simultaneous IPSPs sum to produce a greater IPSP events. Just as squeezing a trigger harder does C Stimulated D Stimulated C 1 D Stimulated 265 265 265 not make the bullet travel faster or farther, stimu- lating a neuron more intensely does not increase 270 270 270 the speed or amplitude of the resulting action 275 275 275 potential. A simultaneous IPSP and EPSP cancel each other out A Stimulated C Stimulated A 1 C Stimulated 265 265 265 Journal Prompt 4.1 270 270 270 Can you think of a metaphor, other than the firing of a gun, that might serve as an accurate 275 275 275 description of the firing of a neuron? M04_PINE1933_11_GE_C04.indd 102 22/01/2021 10:47  Neural Conduction and Synaptic Transmission 103 Figure 4.4 The two possible combinations of temporal summation. A B Inhibitory synapse Excitatory synapse To oscilloscope Two EPSPs elicited in rapid succession sum to produce a larger EPSP 265 265 Membrane potential (millivolts) 270 270 A A A A Two IPSPs elicited in rapid succession sum to produce a larger IPSP 265 265 270 270 B B B B Scan Your Brain This is a good place to pause and scan your brain to check 6. K+ ions are largely held inside the cell because of the your knowledge on synaptic transmission. Fill in the following membrane’s _______ resting potential. blanks with the most appropriate terms. The correct answers 7. _______ pumps ensure that at resting potential, three are provided at the end of the exercise. Before proceeding, Na+ ions move inside the cell and two K+ ions move review material related to your errors and omissions. outside the cell. 1. _______ is a common chemical used to alleviate 8. _______ are released into the synaptic cleft, and they ­symptoms in people living with Parkinson’s disease. attach to receptor molecules on the postsynaptic 2. The difference in electrical charge between the inside ­membrane of the next cell. and outside of a nerve cell is called _______ and is 9. The neurotransmitters may _______ the postsynaptic recorded using microelectrodes. receptive membrane, which implies that the resting 3. The resting potential inside the neuron is approximately membrane potential will increase. _______ mV less than that outside the cell. This is called 10. _______ postsynaptic potentials increase the likelihood polarization. that a neuron will fire. 4. Sodium and potassium ions are both _______ charged. 11. Postsynaptic potentials _______ in amplitude as they 5. In a resting neuron, there are more _______ ions outside travel through the neuron. the cell and more _______ ions inside the cell. M04_PINE1933_11_GE_C04.indd 103 22/01/2021 10:47  104 Chapter 4 12. A momentary increase of membrane potential to about ­ embrane are added, we have _______ m +50 mV is called _______. summation. 13. Each neuron sums the number of excitatory and 16. The firing of neurons and the firing of a gun are both i­nhibitory postsynaptic potentials to create a single _______ responses. ­signal, a process called _______. 14. When postsynaptic potentials that are produced in rapid (16) all-or-none. succession at the same synapse are added, we have (12) action potential, (13) integration, (14) temporal, (15) spatial, _______ summation. (8) Neurotransmitters, (9) hyperpolarize, (10) Excitatory, (11) decrease, 15. When postsynaptic potentials that are produced (3) 70, (4) positively, (5) Na+, K+, (6) negative, (7) Sodium–potassium, ­simultaneously in different parts of the receptive Scan Your Brain answers: (1) L-dopa, (2) membrane potential, large EPSP. The voltage-gated sodium channels in the axon membrane open wide, and Na+ ions rush in, suddenly Conduction of Action reversing the membrane potential; that is, driving the mem- Potentials brane potential from about −70 to about +50 mV. The rapid change in the membrane potential associated with the influx How are action potentials (APs) produced? How are they of Na+ ions then triggers the opening of voltage-gated potas- conducted along the axon? The answer to both questions is sium channels. At this point, K+ ions near the membrane are the same: through the action of voltage-gated ion channels— driven out of the cell through these channels—first by their ion channels that open or close in response to changes in relatively high internal concentration and then, when the membrane potential (see Moran et al., 2015). AP is near its peak, by the positive internal charge. After about 1 millisecond, the sodium channels close. This closure Ionic Basis of Action Potentials marks the end of the rising phase of the AP and the begin- ning of the repolarization phase, which is the result of the LO 4.5 Explain the ionic basis of an action potential. continued efflux of K+ ions. Once repolarization has been Recall that the membrane potential of a neuron at rest is achieved, the potassium channels gradually close, which relatively constant despite the high pressure acting to drive marks the beginning of the hyperpolarization phase. Because Na+ ions into the cell. This is because the resting membrane they close gradually, too many K+ ions flow out of the neu- is relatively impermeable to Na+ ions and because those few ron, and it is left hyperpolarized for a brief period of time. that do pass in are pumped out. But things suddenly change Figure 4.5 illustrates the timing of the opening and closing when the membrane potential of the axon initial segment is of the sodium and potassium channels during an AP, and depolarized to the threshold of excitation by a sufficiently the three associated phases of an AP. Figure 4.5 The opening and closing of voltage-gated sodium and potassium channels during an AP, and the three ­associated phases of an AP. 160 Sodium 150 channels RISING PHASE close 130 REPOLARIZATION Membrane Potential 110 Potassium (millivolts) channels HYPERPOLARIZATION 210 open 230 Sodium Potassium channels channels 250 open start to close 270 1 2 3 4 5 Time (milliseconds) M04_PINE1933_11_GE_C04.indd 104 22/01/2021 10:47  Neural Conduction and Synaptic Transmission 105 The number of ions that flow through the membrane and decrementally. However, when that graded potential ­ uring an AP is extremely small in relation to the total n d ­ umber reaches the next voltage-gated sodium channel along the inside and around the neuron. The AP involves only those axon, and if it is sufficiently large (i.e., it exceeds the thresh- ions right next to the membrane. Therefore, a single AP has old of excitation), then those channels open and Na+ ions little effect on the relative concentrations of various ions inside rush into the axon and generate another full-blown AP. In and outside the neuron, and the resting ion concentrations essence, the AP is continually regenerated at each sodium next to the membrane are rapidly reestablished by the random channel along the length of the axon, again and again until movement of ions. The sodium–­potassium pumps play only a full-blown AP is triggered as the axon terminal buttons. a minor role in the reestablishment of the resting potential. The following analogy may help you appreciate the major characteristics of axonal conduction. Consider a row of mouse traps on a wobbly shelf, all of them set and ready Refractory Periods to be triggered. Each trap stores energy by holding back its LO 4.6 Explain how the refractory period is responsible striker against the pressure of the spring, in the same way for two important characteristics of neural activity. that each voltage-gated sodium channel stores energy by holding back Na+ ions, which are under pressure to move There is a brief period of about 1 to 2 milliseconds after the down their concentration and electrostatic gradients into initiation of an AP during which it is impossible to elicit the neuron. When the first trap in the row is triggered, the a second AP. This period is called the absolute refractory vibration is transmitted through the shelf rapidly and decre- period. The absolute refractory period is followed by the mentally. When the vibration reaches the next trap and it is relative refractory period—the period during which it sufficiently large, then that trap is sprung—and so on down is possible to fire the neuron again but only by applying the line. Likewise, when a sodium channel at the axon initial higher-than-normal levels of stimulation. The end of the rel- segment is opened by an EPSP, an AP is generated and then ative refractory period is the point at which the amount of that electrical signal travels instantly and decrementally stimulation necessary to fire the neuron returns to baseline. (i.e., as a graded potential) to the next sodium channel along Refractory periods are responsible for two important the axon. Then, that sodium channel opens to generate an characteristics of neural activity. First, they are responsible AP, and so on down the length of the axon. for the fact that APs normally travel along axons in only one direction. Because the portions of an axon over which an AP has just traveled are left momentarily refractory, an AP can- Journal Prompt 4.2 not reverse direction. Second, refractory periods are respon- Can you think of a better analogy to describe axonal sible for the fact that the rate of neural firing is related to the conduction? intensity of the stimulation. If a neuron is subjected to con- tinual high-intensity stimulation, it fires and then fires again as soon as its absolute refractory period is over—a maximum The nondecremental nature of AP conduction is read- of about 1,000 times per second. However, if the level of con- ily apparent from this analogy; the last trap on the shelf tinuous stimulation is of an intensity just sufficient to fire the strikes with no less intensity than did the first. This anal- neuron when it is at rest, the neuron does not fire again until ogy also illustrates another important point: The row of both the absolute and the relative refractory periods have run traps can transmit in either direction, just like an axon. If their course. Intermediate intensities of continuous stimula- electrical stimulation of sufficient intensity is applied to a tion produce intermediate rates of neural firing. midpoint of an axon, two APs will be generated: One AP will travel along the axon back to the cell body—this is Axonal Conduction of Action called a­ ntidromic conduction; the second AP will travel along the axon towards the terminal buttons—this is called Potentials orthodromic conduction. The elicitation of an AP and its LO 4.7 Describe how action potentials are conducted orthodromic conduction are illustrated in Figure 4.6. along axons—both myelinated and unmyelinated. The generation of an AP at the axon initial segment also spreads back through the cell body and dendrites of the The conduction of APs along an axon differs from the con- neuron as a large graded potential. It is believed that these duction of PSPs in two important ways. First, the conduc- antidromic (backpropagating) potentials play a role in certain tion of APs along an axon is typically nondecremental; APs forms of synaptic plasticity (see Stuart & Spruston, 2015). do not grow weaker as they travel along the axonal mem- brane. Second, APs are conducted more slowly than PSPs. CONDUCTION IN MYELINATED AXONS. Recall that the These two differences are the result of the important axons of many neurons are insulated from the extracellular role played by voltage-gated sodium channels in AP con- fluid by segments of fatty tissue called myelin. In myelinated duction. Once an AP has been generated, it travels along axons, ions can pass through the axonal membrane only at the the axon as a graded potential; that is, it travels rapidly nodes of Ranvier—the gaps between adjacent myelin segments. M04_PINE1933_11_GE_C04.indd 105 22/01/2021 10:47  106 Chapter 4 the signal “jumps” along the axon from Figure 4.6 The usual direction of signals conducted through a multipolar neuron (i.e., orthodromic conduction). one node of Ranvier to the next. There is, of course, a slight delay at each node while the AP is regenerated, but con- 1 Postsynaptic potentials (PSPs) are elicited on the cell body and dendrites. duction is still much faster in myelin- ated axons than in unmyelinated axons. The transmission of APs in myelinated axons is called ­saltatory conduction (saltare means “to skip or jump”). Given 2 PSPs are conducted decrementally to the axon initial segment. the important role of myelin in neural conduction, it is hardly surprising that diseases that damage the nervous sys- tem by attacking myelin, like multiple sclerosis, have devastating effects on neural activity and behavior. THE VELOCITY OF AXONAL 3 When the summated CONDUCTION. At what speed are PSPs exceed the threshold APs conducted along an axon? The of excitation at the axon initial segment, answer to this question depends on an action potential (AP) is triggered. two properties of the axon. Conduction is faster in large-diameter axons, and— as you have just learned—it is faster in those that are myelinated. Human motor neurons (neurons that synapse on skeletal muscles) are large and myelin- ated; thus, some can conduct at speeds 4 The AP is conducted nondecrementally down the axon to the terminal button up to 60 meters per second (about 134 miles per hour). In contrast, small, (orthodromic conduction). unmyelinated axons conduct APs at about 1 meter per second. CONDUCTION IN NEURONS WITHOUT AXONS. APs are the means by which axons conduct all-or-none sig- 5 Arrival of the AP at the terminal button triggers exocytosis. nals nondecrementally over relatively long distances. Thus, to keep what you have just learned about APs in perspec- tive, it is important for you to remember that most neurons in mammalian brains either do not have axons or have very Indeed, in myelinated axons, axonal voltage-gated sodium short ones, and many of these neurons do not normally dis- channels are concentrated at the nodes of Ranvier. How, play APs. Conduction in these interneurons is typically only then, are APs transmitted in myelinated axons? through graded potentials. If we consider the mouse trap metaphor again, the answer is quite simple: It is just as if the mouse traps were placed further apart along the wobbly shelf. That is, because The Hodgkin-Huxley Model the sodium channels are concentrated at some distance from in Perspective one another (at the nodes of Ranvier), the electrical signal LO 4.8 Explain the shortcomings of the Hodgkin- generated at the sodium channels at one node of Ranvier Huxley model when applied to neurons in the travels instantly and decrementally (i.e., it is a graded mammalian brain. potential) to the sodium channels at the next node, and so on down the length of the myelinated axon. The preceding account of neural conduction is based largely Myelination increases the speed of axonal conduc- on the Hodgkin-Huxley model, the theory first proposed by tion. Because conduction along the myelinated segments Hodgkin and Huxley in the early 1950s (see Catterall et al., of the axon is instantaneous (i.e., it is a graded potential), 2012). Perhaps you have previously encountered some of M04_PINE1933_11_GE_C04.indd 106 22/01/2021 10:47  Neural Conduction and Synaptic Transmission 107 this information about neural conduction in introductory how neurotransmitters carry signals to other cells. This ­module biology or psychology courses, where it is often presented as provides an overview of five aspects of synaptic transmission: a factual account of neural conduction and its mechanisms, (1) the structure of synapses; (2) the synthesis, packaging, and rather than as a theory. To be fair, the Hodgkin-Huxley transport of neurotransmitter molecules; (3) the release of model was a major advance in our understanding of neu- neurotransmitter molecules; (4) the activation of receptors by ral conduction (Catterall et al., 2012). Fully deserving of the neurotransmitter molecules; and (5) the reuptake, enzymatic 1963 Nobel Prize, the model provided a simple, effective degradation, and recycling of neurotransmitter molecules. introduction to what we now understand about the general ways in which neurons conduct signals. The problem is that Structure of Synapses the simple neurons and mechanisms of the Hodgkin-Huxley LO 4.9 Describe the structure of different types of model are not representative of the variety, complexity, and synapses. plasticity of many of the neurons in the mammalian brain. The Hodgkin-Huxley model was based on the study Some communication among neurons occurs across synapses of squid motor neurons. Motor neurons are simple, large, such as the one illustrated in Figure 4.7. At such synapses, and readily accessible in the PNS—squid motor neurons neurotransmitter molecules are released from specialized are particularly large. The simplicity, size, and accessibility sites on buttons into synaptic clefts, where they induce of squid motor neurons contributed to the initial success of EPSPs or IPSPs in other neurons by binding to receptors Hodgkin’s and Huxley’s research, but these same properties on their postsynaptic membranes. The synapse featured in make it difficult to apply the model directly to the mamma- Figure 4.7 is an ­axodendritic synapse—a synapse of an axon lian brain. Hundreds of different kinds of neurons are found terminal button onto a dendrite. Also common are a­ xosomatic in the mammalian brain, and many of these have actions not synapses—-synapses of axon terminal buttons on somas (cell found in motor neurons. bodies). Notice in Figure 4.7 that many axodendritic syn- Moreover, there is mounting evidence that neural con- apses terminate on dendritic spines (nodules of various duction is not merely due to electrical impulses (see Holland, shapes that are located on the surfaces of many dendrites)— De Regt, & Drukarch, 2019). For example, there is evidence see Figure 3.30. Also notice in Figure 4.7 that an astrocyte is that electrical impulses, like APs or PSPs, are accompa- situated at the synapse. Most synapses in the brain form a nied by mechanical impulses: travelling waves of expan- ­tripartite synapse: a synapse that involves two neurons and sion and contraction of the neural ­membrane—exactly like ripples on Figure 4.7 Anatomy of a typical synapse. a pond (see Fox, 2018). In summary, the Hodgkin-Huxley model should Microtubules be applied to cerebral neurons with Synaptic great caution. vesicles Synaptic Transmission: From Electrical Signals to Golgi Chemical Signals complex Now that you have learned about how communication occurs within Button a single neuron—through postsyn- aptic potentials (PSPs) and action Mitochondrion potentials (APs)—you are ready to learn how neurons communicate Astrocytic process with other cells. In the remaining modules of this chapter, you will Dendritic spine learn how APs arriving at terminal buttons trigger the release of neu- Presynaptic Synaptic Astrocytic Postsynaptic membrane cleft process membrane rotransmitters into synapses and M04_PINE1933_11_GE_C04.indd 107 22/01/2021 10:47  108 Chapter 4 an astroglial cell (see Allen & Eroglu, Figure 4.8 Presynaptic facilitation and inhibition. 2017; Grosche & Reichenbach, 2013; Navarrete & Araque, 2014; Sun et al., Axoaxonic 2013). All three cells communicate synapse B with one another through synaptic transmission. C Although axodendritic and axosomatic synapses are the most common synaptic arrange- ments, there are many others (see A M atthews & Fuchs, 2010). For ­ example, there are dendrodendritic synapses, which are interesting Neuron A synapses on the terminal button of neuron B. because they are often capable of Some such axoaxonic synapses increase the effects of one transmission in either direction neuron (B) on another (C) (presynaptic facilitation); others (see Urban & Castro, 2010). There decrease the effects of one neuron (B) on another (C) (presynaptic inhibition). The advantage of presynaptic are also axoaxonic synapses; these facilitation and inhibition is that they selectively influence are particularly important because single synapses, rather than the entire neuron. they can mediate presynaptic facilita- tion and inhibition. As illustrated in Figure 4.8, an axoaxonic synapse on or near a terminal button can selectively facilitate or inhibit the effects of that button on the post- synaptic neuron. The advantage of presynaptic facilitation and inhibi- Figure 4.9 One example of nondirected neurotransmitter release. Some neurons tion (compared to PSPs) is that they release neurotransmitter molecules diffusely from varicosities along the axon and its can selectively influence one partic- branches. ular synapse rather than the entire presynaptic neuron. Finally, in the central nervous system, there are also axomyelenic synapses, where an axon synapses on the myelin sheath of an oligodendrocyte. This newly discovered type of synapse repre- sents yet another form of neuron– glia communication (see Dimou & Neurotransmitter Simons, 2017; Micu et al., 2018). Varicosity molecules The synapses depicted in ­Figures 4.7 and 4.8 are directed ­synapses—synapses at which the site of neurotransmitter release and the site of neurotransmitter recep- tion are in close proximity. This is a common arrangement, but there are also many nondirected synapses in the ­ mammalian nervous system. ­Nondirected synapses are synapses at which the site of release is at some distance from the site of reception. One type of nondirected synapse is depicted in Figure 4.9. In this type of arrangement, neurotransmitter M04_PINE1933_11_GE_C04.indd 108 22/01/2021 10:47  Neural Conduction and Synaptic Transmission 109 molecules are released from a series of varicosities (bulges or is at rest, synaptic vesicles that contain small-molecule swellings) along the axon and its branches and thus are widely neurotransmitters tend to congregate near sections of dispersed to surrounding targets. Because of their appearance, the presynaptic membrane that are particularly rich in these synapses are often referred to as string-of-beads synapses. ­voltage-gated calcium channels (see Simms & Zamponi, 2014). When stimulated by APs, these channels open, and Ca2+ Synthesis, Packaging, and Transport (calcium) ions enter the button. The entry of the Ca2+ ions of Neurotransmitter Molecules triggers a chain reaction that ultimately causes synaptic vesicles to fuse with the presynaptic membrane and empty LO 4.10 Describe how neurotransmitter molecules are their ­contents into the synaptic cleft (see Zhou et al., 2017). synthesized and packaged in vesicles. The release of small-molecule neurotransmitters differs There are two basic categories of neurotransmitter mole- from the release of neuropeptides. Small-molecule neu- cules: large and small. rotransmitters are typically released in a pulse each time an All large neurotransmitters are neuropeptides. AP triggers a momentary influx of Ca2+ ions into the pre- ­Neuropeptides are short amino acid chains composed of synaptic membrane; in contrast, neuropeptides are typically between 3 and 36 amino acids; in effect, they are short proteins. released gradually in response to general increases in the Small-molecule neurotransmitters are typically syn- level of intracellular Ca2+ ions, such as might occur during thesized in the cytoplasm of the terminal button and pack- a general increase in the rate of neuron firing. aged in synaptic vesicles by the button’s Golgi complex. It is important to note that not all vesicles fuse with (This may be a good point at which to review the internal the presynaptic membrane. Some vesicles are released structures of neurons in Figure 3.6.) Once filled with neu- as intact packages into the extracellular space. These rotransmitter, the vesicles are stored in clusters next to the extracellular vesicles often carry larger molecules (e.g., presynaptic membrane. In contrast, neuropeptides, like proteins, RNA molecules) between different neurons and other proteins, are assembled in the cytoplasm of the cell glia in the central nervous system (see Holm, ­Kaiser, & body on ribosomes; they are then packaged in vesicles by the Schwab, 2018; Paolicelli, Bergamini, & Rajendran, 2018). cell body’s Golgi complex and transported by microtubules to Some of these transmitted molecules can induce per- the terminal buttons at a rate of about 40 centimeters (about sistent changes in the expression of genes through epi- 16 inches) per day. The vesicles that contain neuropeptides genetic mechanisms (see Bakhshandeh, Kamaleddin, & are usually larger than those that contain small-molecule Aalishah, 2017). neurotransmitters, and they do not usually congregate as closely to the presynaptic membrane as the other vesicles do. It was once believed that each neuron synthesizes and Activation of Receptors by releases only one neurotransmitter, but it has been clear for Neurotransmitter Molecules some time that many neurons contain two neurotransmitters— LO 4.12 Describe the differences between ionotropic a situation generally referred to as coexistence. It may have and metabotropic receptors. escaped your notice that the button illustrated in F ­ igure 4.7 contains synaptic vesicles of two sizes. This suggests that it Once released, neurotransmitter molecules produce sig- contains two neurotransmitters: a neuropeptide in the larger nals in postsynaptic neurons by binding to receptors in vesicles and a small-molecule neurotransmitter in the smaller the postsynaptic membrane. Each receptor is a protein that vesicles. Although this type of coexistence was the first to be contains binding sites for only particular neurotransmitters; discovered, we now know that there is also coexistence of mul- thus, a neurotransmitter can influence only those cells that tiple small-molecule neurotransmitters in the same neuron (see have receptors for it. Any molecule that binds to another is Granger, Wallace, & Sabatini, 2017). Adding to the complexity referred to as its ligand, and a neurotransmitter is thus said is the fact that neurons can change the types of neurotransmit- to be a ligand of its receptor. ters they release over their lifespan (see Spitzer, 2017). It was initially assumed that there is only one type of receptor for each neurotransmitter, but this has not proved to be the case. As more receptors have been identified, it Release of Neurotransmitter has become clear that most neurotransmitters bind to Molecules several different types of receptors. The different types of receptors to which a particular neurotransmitter can bind LO 4.11 Explain the process of neurotransmitter are called the receptor subtypes for that n ­ eurotransmitter. exocytosis. The various receptor subtypes for a neurotransmitter are Exocytosis—the process of neurotransmitter release—is typically located in different brain areas, and they typi- illustrated in Figure 4.10 (see Shin, 2014). When a neuron cally respond to the neurotransmitter in different ways. M04_PINE1933_11_GE_C04.indd 109 22/01/2021 10:47  110 Chapter 4 Figure 4.10 Schematic illustration of exocytosis. Presynaptic Postsynaptic membrane membrane Don W. Fawcett/Science Source Thus, one advantage of receptor subtypes is that they flow of K+ ions out of the neuron or the flow of Cl− ions into enable one neurotransmitter to transmit different kinds of it, respectively. messages to different parts of the brain. Metabotropic receptors are more prevalent than iono- The binding of a neurotransmitter to one of its recep- tropic receptors, and their effects are slower to develop, tor subtypes can influence a postsynaptic neuron in one of longer-lasting, more diffuse, and more varied. There are two fundamentally different ways, depending on whether many different kinds of metabotropic receptors, but each is the receptor is ionotropic or metabotropic. Ionotropic attached to a serpentine signal protein that winds its way ­receptors are associated with ligand-activated ion channels; back and forth through the cell membrane seven times. The ­metabotropic receptors are typically associated with sig- metabotropic receptor is attached to a portion of the signal nal proteins and G proteins (guanosine-triphosphate−sensitive protein outside the neuron; the G protein is attached to a proteins); see Figure 4.11. portion of the signal protein inside the neuron. When a neurotransmitter molecule binds to an iono- When a neurotransmitter binds to a metabotropic recep- tropic receptor, the associated ion channel usually opens or tor, a subunit of the associated G protein breaks away. Then, closes immediately, thereby inducing an immediate post- one of two things happen, depending on the particular synaptic potential. For example, in some neurons, EPSPs G protein. The subunit may move along the inside surface (depolarizations) occur because the neurotransmitter opens of the membrane and bind to a nearby ion channel, thereby sodium channels, thereby increasing the flow of Na+ ions inducing an EPSP or IPSP; or it may trigger the synthesis into the neuron. In contrast, IPSPs (hyperpolarizations) of a chemical called a second messenger (neurotransmit- often occur because the neurotransmitter opens potassium ters are considered to be the first messengers). Once created, channels or chloride (Cl−) channels, thereby increasing the a second messenger diffuses through the cytoplasm and M04_PINE1933_11_GE_C04.indd 110 22/01/2021 10:47  Neural Conduction and Synaptic Transmission 111 interest to researchers. For example, there is Figure 4.11 Ionotropic and metabotropic receptors. strong evidence that the structures of both types of receptors (and thus their functionality) An Ionotropic Receptor can be altered through epigenetic mechanisms Ion (see Fomsgaard et al., 2018). Moreover, certain Neurotransmitter disorders may be the result of modifications to Ionotropic receptor structure via epigenetic mechanisms receptor (see Matosin et al., 2017). Closed One type of metabotropic receptor— ion channel autoreceptors—warrants special mention. ­Autoreceptors are metabotropic receptors that have two unconventional characteristics: They bind to their neuron’s own neurotransmitter molecules, and they are located on the presyn- aptic, rather than the postsynaptic, membrane. Their usual function is to monitor the number of neurotransmitter molecules in the synapse, to reduce subsequent release when the levels Some neurotransmitter molecules bind to receptors on ion channels. When are high, and to increase subsequent release a neurotransmitter molecule binds to an ionotropic receptor, the channel opens (as in this case) or closes, thereby altering the flow of ions into or out when they are low. of the neuron. Differences between small-molecule and peptide neurotransmitters in patterns of release and receptor binding suggest A Metabotropic Receptor that they serve different functions. Small-­ Neurotransmitter molecule neurotransmitters tend to be Metabotropic receptor released into directed synapses and to acti- Signal vate either ionotropic receptors or metabo- protein tropic receptors that act directly on ion channels. In contrast, neuropeptides tend to be released diffusely, and virtually all bind to metabotropic receptors that act through sec- ond messengers. Consequently, the function of small-molecule neurotransmitters appears to be the transmission of rapid, brief excit- G protein atory or inhibitory signals to adjacent cells; and the function of neuropeptides appears to be the transmission of slow, diffuse, long- Some neurotransmitter molecules bind to receptors on membrane lasting signals. signal proteins, which are linked to G proteins. When a neurotrans- mitter molecule binds to a metabotropic receptor, a subunit of the G protein breaks off into the neuron and either binds to an ion channel or stimulates the synthesis of a second messenger. Reuptake, Enzymatic Degradation, and Recycling LO 4.13 Explain how neurotransmitters are may influence the activities of the neuron in a variety of removed from a synapse. ways (Lyon, Taylor, & Tesmer, 2014)—for example, it may enter the nucleus and bind to the DNA, thereby influenc- If nothing intervened, a neurotransmitter molecule ing genetic expression. Thus, a neurotransmitter’s binding would remain active in the synapse, in effect clogging to a metabotropic receptor can have radical, long-lasting that channel of communication. However, two mecha- effects. Furthermore, there is now evidence that ionotropic nisms terminate synaptic messages and keep that from receptors can also produce second messengers that can happening. These two message-terminating mechanisms have enduring effects (see Valbuena & Lerma, 2016; Reiner are ­reuptake by transporters and enzymatic degradation & Levitz, 2018). (see Figure 4.12). Epigenetic mechanisms (see Chapter 2) that act on both Reuptake is the more common of the two deactivat- ionotropic and metabotropic receptors are of increasing ing mechanisms. The majority of neurotransmitters, once M04_PINE1933_11_GE_C04.indd 111 22/01/2021 10:47  112 Chapter 4 Figure 4.12 The two mechanisms for terminating neurotransmitter action in the synapse: reuptake and enzymatic degradation. Two Mechanisms of Neurotransmitter Deactivation in Synapses Neurotransmitter Transporter Deactivating molecule enzyme Reuptake Enzymatic Degradation released, are almost immediately drawn back into the pre- The explosion of interest in the role of glial cells in synaptic buttons by transporter mechanisms. brain function has gone hand in hand with an increased In contrast, other neurotransmitters are degraded interest in the role of gap junctions. Gap junctions are nar- (broken apart) in the synapse by the action of enzymes—­ row spaces between adjacent cells that are bridged by fine, proteins that stimulate or inhibit biochemical reactions tubular, cytoplasm-filled protein channels, called connexins. without being affected by them. For example, acetylcholine, Consequently, gap junctions connect the cytoplasm of two one of the few neurotransmitters for which enzymatic deg- adjacent cells, allowing electrical signals and small mole- radation is the main mechanism of synaptic deactivation, is cules (e.g., second messengers) to pass from one cell to the broken down by the enzyme acetylcholinesterase. next (see Figure 4.13). Gap junctions are re