Module 19: Organization of the Nervous System PDF

CHAPTER 46 Organization of the Nervous System, Basic Functions of Synapses, and UNIT IX...

CHAPTER 46 Organization of the Nervous System, Basic Functions of Synapses, and UNIT IX Neurotransmitters The nervous system is unique in the vast complexity of of receptors. These sensory experiences can either cause thought processes and control actions that it can perform. immediate reactions from the brain, or memories of the Each minute it receives literally millions of bits of informa- experiences can be stored in the brain for minutes, weeks, tion from the different sensory nerves and sensory organs or years and determine bodily reactions at some future and then integrates all these to determine responses to be date. made by the body. Figure 46-2 shows the somatic portion of the sen- Before beginning this discussion of the nervous sys- sory system, which transmits sensory information from tem, the reader should review Chapters 5 and 7, which the receptors of the entire body surface and from some present the principles of membrane potentials and trans- deep structures. This information enters the central mission of signals in nerves and through neuromuscular nervous system through peripheral nerves and is con- junctions. ducted immediately to multiple sensory areas in (1) the spinal cord at all levels; (2) the reticular substance of the medulla, pons, and mesencephalon of the brain; (3) GENERAL DESIGN OF THE NERVOUS the cerebellum; (4) the thalamus; and (5) areas of the SYSTEM cerebral cortex.! CENTRAL NERVOUS SYSTEM NEURON: MOTOR PART OF THE NERVOUS THE BASIC FUNCTIONAL UNIT SYSTEM—EFFECTORS The central nervous system is estimated to contain 80 to The most important eventual role of the nervous sys- 100 billion neurons. Figure 46-1 shows a typical neuron of tem is to control the various bodily activities. This task a type found in the brain motor cortex. Incoming signals is achieved by controlling (1) contraction of appropriate enter this neuron through synapses located mostly on the skeletal muscles throughout the body; (2) contraction of neuronal dendrites, but also on the cell body. For different smooth muscle in the internal organs; and (3) secretion types of neurons, there may be only a few hundred or as of active chemical substances by both exocrine and endo- many as 200,000 such synaptic connections from input crine glands in many parts of the body. These activities are fibers. In contrast, the output signal travels via a single collectively called motor functions of the nervous system, axon leaving the neuron. Then, this axon may have many and the muscles and glands are called effectors because separate branches to other parts of the nervous system or they are the actual anatomical structures that perform the peripheral body. functions dictated by the nerve signals. A special feature of most synapses is that the signal Figure 46-3 shows the “skeletal” motor nerve axis of normally passes only in the forward direction, from the the nervous system for controlling skeletal muscle con- axon of a preceding neuron to dendrites on cell mem- traction. Operating parallel to this axis is another sys- branes of subsequent neurons. This feature forces the tem, called the autonomic nervous system, for controlling signal to travel in required directions to perform specific smooth muscles, glands, and other internal bodily sys- nervous functions.! tems; this system is discussed in Chapter 61. Note in Figure 46-3 that the skeletal muscles can be SENSORY PART OF THE NERVOUS controlled from many levels of the central nervous sys- SYSTEM—SENSORY RECEPTORS tem, including (1) the spinal cord; (2) the reticular sub- Most activities of the nervous system are initiated by sen- stance of the medulla, pons, and mesencephalon; (3) sory experiences that excite sensory receptors, whether the basal ganglia; (4) the cerebellum; and (5) the motor visual receptors in the eyes, auditory receptors in the ears, cortex. Each of these areas has its own specific role. The tactile receptors on the surface of the body, or other types lower regions are concerned primarily with automatic, 569 UNIT IX The Nervous System: A. General Principles and Sensory Physiology Somesthetic areas Motor cortex Dendrites Thalamus Brain Bulboreticular formation Cell body Pons Cerebellum Medulla Skin Pain, cold, Spinal cord warmth (free nerve ending) Pressure (Pacinian corpuscle) (expanded tip receptor) Touch (Meissner's corpuscle) Muscle spindle Axon Golgi tendon apparatus Muscle Kinesthetic receptor Synapses Joint Spinal cord Second-order Figure 46-2. Somatosensory axis of the nervous system. neurons is called the integrative function of the nervous system. Figure 46-1. Structure of a large neuron in the brain showing its Thus, if a person places a hand on a hot stove, the desired important functional parts. instantaneous response is to lift the hand. Other associ- ated responses follow, such as moving the entire body instantaneous muscle responses to sensory stimuli, and away from the stove and perhaps even shouting with pain.! the higher regions are concerned with deliberate complex ROLE OF SYNAPSES IN PROCESSING muscle movements controlled by thought processes of INFORMATION the brain.! The synapse is the junction point from one neuron to the PROCESSING OF INFORMATION— next. Later in this chapter, we discuss the details of syn- INTEGRATIVE FUNCTION OF THE aptic function. However, it is important to note here that NERVOUS SYSTEM synapses determine the directions that the nervous sig- One of the most important functions of the nervous sys- nals will spread through the nervous system. Some syn- tem is to process incoming information in such a way that apses transmit signals from one neuron to the next with appropriate mental and motor responses will occur. More ease, whereas others transmit signals only with difficulty. than 99% of all sensory information is discarded by the Also, facilitatory and inhibitory signals from other areas brain as irrelevant and unimportant. For example, one is in the nervous system can control synaptic transmission, ordinarily unaware of the parts of the body that are in con- sometimes opening the synapses for transmission and, at tact with clothing, as well as the seat pressure when sitting. other times, closing them. In addition, some postsynaptic Likewise, attention is drawn only to an occasional object neurons respond with large numbers of output impulses, in one’s field of vision, and even the perpetual noise of our and others respond with only a few. Thus, the synapses surroundings is usually relegated to the subconscious. perform a selective action, often blocking weak signals However, when important sensory information excites while allowing strong signals to pass but, at other times, the mind, it is immediately channeled into proper inte- selecting and amplifying certain weak signals and often grative and motor regions of the brain to cause desired channeling these signals in many directions rather than in responses. This channeling and processing of information only one direction.! 570  Chapter 46 Organization of the Nervous System, Basic Functions of Synapses, and Neurotransmitters Motor nerve Motor Once memories have been stored in the nervous sys- to muscles area tem, they become part of the brain processing mechanism for future “thinking.” That is, the thinking processes of Caudate the brain compare new sensory experiences with stored nucleus memories; the memories then help select the important UNIT IX new sensory information and channel this into appropri- ate memory storage areas for future use or into motor areas to cause immediate bodily responses.! MAJOR LEVELS OF CENTRAL NERVOUS Thalamus SYSTEM FUNCTION Putamen Globus pallidus The human nervous system has inherited special func- Subthalamic nucleus tional capabilities from each stage of human evolution- Bulboreticular formation ary development. From this heritage, three major levels Cerebellum of the central nervous system have specific functional characteristics: (1) the spinal cord level; (2) the lower brain or subcortical level; and (3) the higher brain or cor- tical level. SPINAL CORD LEVEL Gamma motor fiber Alpha motor fiber We often think of the spinal cord as being only a conduit for signals from the periphery of the body to the brain or in the opposite direction from the brain back to the body. This supposition is far from the truth. Even after the spi- Muscle spindle nal cord has been cut in the high neck region, many highly Stretch receptor fiber Figure 46-3. Skeletal motor nerve axis of the nervous system. organized spinal cord functions still occur. For example, neuronal circuits in the cord can cause (1) walking move- ments; (2) reflexes that withdraw portions of the body STORAGE OF INFORMATION—MEMORY away from painful objects; (3) reflexes that stiffen the legs Only a small fraction of even the most important sensory to support the body against gravity; and (4) reflexes that information usually causes immediate motor response. control local blood vessels, gastrointestinal movements, However, much of the information is stored for future or urinary excretion. In fact, the upper levels of the ner- control of motor activities and for use in the thinking vous system often operate not by sending signals directly processes. Most storage occurs in the cerebral cortex, but to the periphery of the body, but by sending signals to even the basal regions of the brain and the spinal cord can the control centers of the cord, simply “commanding” the store small amounts of information. cord centers to perform their functions.! The storage of information is the process we call mem- ory, which is also a function of the synapses. Each time certain types of sensory signals pass through sequences of LOWER BRAIN OR SUBCORTICAL LEVEL synapses, these synapses become more capable of trans- Many, if not most, of what we call subconscious activi- mitting the same type of signal the next time, a process ties of the body are controlled in the lower areas of the called facilitation. After the sensory signals have passed brain—that is, in the medulla, pons, mesencephalon, through the synapses a large number of times, the syn- hypothalamus, thalamus, cerebellum, and basal ganglia. apses become so facilitated that signals generated within For example, subconscious control of arterial pressure the brain itself can also cause transmission of impulses and respiration is achieved mainly in the medulla and through the same sequences of synapses, even when pons. Control of equilibrium is a combined function of the sensory input is not excited. This process gives the the older portions of the cerebellum and the reticular sub- person a perception of experiencing the original sensa- stance of the medulla, pons, and mesencephalon. Feeding tions, although the perceptions are only memories of the reflexes, such as salivation and licking the lips in response sensations. to the taste of food, are controlled by areas in the medulla, The precise mechanisms whereby long-term facilita- pons, mesencephalon, amygdala, and hypothalamus. In tion of synapses occurs in the memory process are still addition, many emotional patterns, such as anger, excite- uncertain, but what is known about this and other details ment, sexual response, reaction to pain, and reaction to of the sensory memory process are discussed in Chapter pleasure, can still occur after destruction of much of the 58. cerebral cortex.! 571 UNIT IX The Nervous System: A. General Principles and Sensory Physiology Problem HIGHER BRAIN OR CORTICAL LEVEL After the preceding account of the many nervous system Input Output Answer functions that occur at the cord and lower brain levels, one may ask, “what is left for the cerebral cortex to do?” The answer to this question is complex, but it begins with Procedure Initial Result of the fact that the cerebral cortex is an extremely large for solution data operations Information memory storehouse. The cortex never functions alone storage but always in association with lower centers of the ner- vous system. Central Computational Without the cerebral cortex, the functions of the lower processing unit unit brain centers are often imprecise. The vast storehouse of cortical information usually converts these functions to Figure 46-4. Block diagram of a general-purpose computer showing determinative and precise operations. the basic components and their interrelations. Finally, the cerebral cortex is essential for most of our thought processes, but it cannot function by itself. In fact, CENTRAL NERVOUS SYSTEM SYNAPSES it is the lower brain centers, not the cortex, that initiate wakefulness in the cerebral cortex, thereby opening its Information is transmitted in the central nervous sys- bank of memories to the thinking machinery of the brain. tem mainly in the form of nerve action potentials, Thus, each portion of the nervous system performs spe- called nerve impulses, through a succession of neu- cific functions, but it is the cortex that opens a world of rons, one after another. However, each impulse (1) stored information for use by the mind.! may be blocked in its transmission from one neuron to the next; (2) may be changed from a single impulse into repetitive impulses; or (3) may be integrated with COMPARISON OF THE NERVOUS impulses from other neurons to cause highly intricate SYSTEM TO A COMPUTER patterns of impulses in successive neurons. All these It is readily apparent that computers have many features functions can be classified as synaptic functions of in common with the nervous system. First, all computers neurons. have input circuits that can be compared with the sensory portion of the nervous system, as well as output circuits TYPES OF SYNAPSES—CHEMICAL AND that are analogous to the motor portion of the nervous ELECTRICAL system. In simple computers, the output signals are con- There are two major types of synapses (Figure 46-5)—(1) trolled directly by the input signals, operating in a man- chemical and (2) electrical. ner similar to that of simple reflexes of the spinal cord. In Most of the synapses used for signal transmission in more complex computers, the output is determined by the central nervous system of the human being are chemi- input signals and by information that has already been cal synapses. In these synapses, the first neuron secretes stored in memory in the computer, which is analogous at its nerve ending synapse a chemical substance called to the more complex reflex and processing mechanisms a neurotransmitter (often called a transmitter substance), of the human higher nervous system. Furthermore, as and this transmitter in turn acts on receptor proteins in computers become even more complex, it is necessary the membrane of the next neuron to excite the neuron, to add still another unit, called the central processing inhibit it, or modify its sensitivity in some other way unit, which determines the sequence of all operations. (Video 46-1). More than 50 important neurotransmitters This unit is analogous to the control mechanisms in the have been discovered thus far. Some of the best known are brain that direct a person’s attention first to one thought acetylcholine, norepinephrine, epinephrine, histamine, or sensation or motor activity, then to another, and so gamma-aminobutyric acid (GABA), glycine, serotonin, forth, until complex sequences of thought or action take and glutamate. place. In electrical synapses, the cytoplasms of adjacent cells Figure 46-4 is a simple block diagram of a computer. are directly connected by clusters of ion channels called Even a rapid study of this diagram demonstrates its simi- gap junctions that allow free movement of ions from the larity to the nervous system. The fact that the basic com- interior of one cell to the interior of the next cell. Such ponents of the general purpose computer are analogous junctions were discussed in Chapter 4, and it is by way to those of the human nervous system demonstrates that of gap junctions and other similar junctions that action the brain has many features of a computer, continuously potentials are transmitted from one smooth muscle fiber collecting sensory information and using this, along with to the next in visceral smooth muscle (Chapter 8) and stored information, to compute the daily course of bodily from one cardiac muscle cell to the next in cardiac muscle activity.! (Chapter 9). 572  Chapter 46 Organization of the Nervous System, Basic Functions of Synapses, and Neurotransmitters A Chemical synapse istic that makes them highly desirable for transmitting nervous system signals. This characteristic is that they Action always transmit the signals in one direction—that is, from potential Mitochondria the neuron that secretes the neurotransmitter, called the presynaptic neuron, to the neuron on which the transmit- Ca2+ UNIT IX ter acts, called the postsynaptic neuron. This phenomenon Synaptic is the principle of one-way conduction at chemical synaps- Presynaptic vesicle es, and it is different from conduction through electrical terminal synapses, which often transmit signals in either direction. A one-way conduction mechanism allows signals to Neurotransmitter be directed toward specific goals. Indeed, it is this spe- Synaptic cleft cific transmission of signals to discrete and highly focused (200-300 Å) areas both within the nervous system and at the terminals of the peripheral nerves that allows the nervous system to Ionotropic Metabotropic perform its myriad functions of sensation, motor control, receptor receptor Ions Second memory, and many other functions.! Postsynaptic messenger terminal Cellular response: PHYSIOLOGIC ANATOMY OF THE Membrane potential SYNAPSE Biochemical cascades Regulation of gene expression Figure 46-6 shows a typical anterior motor neuron in the anterior horn of the spinal cord. It is composed of three major parts—the soma, which is the main body of the B Electrical synapse neuron, a single axon, which extends from the soma into Action a peripheral nerve that leaves the spinal cord, and den- potential drites, which are great numbers of branching projections of the soma that extend as much as 1 millimeter into the surrounding areas of the cord. Presynaptic As many as 10,000 to 200,000 minute synaptic knobs terminal called presynaptic terminals lie on the surfaces of the den- Gap junction channels drites and soma of the motor neuron, with about 80% to 95% of them on the dendrites and only 5% to 20% on the Intercellular soma. These presynaptic terminals are the ends of nerve gap (20-40 Å) fibrils that originate from many other neurons. Many of these presynaptic terminals are excitatory—that is, they secrete a neurotransmitter that excites the postsynaptic neuron. However, other presynaptic terminals are inhibi- Postsynaptic tory—that is, they secrete a neurotransmitter that inhibits terminal the postsynaptic neuron. Neurons in other parts of the cord and brain differ from the anterior motor neuron in (1) the size of the cell Figure 46-5. Physiologic anatomy of (A) chemical synapse and (B) body; (2) the length, size, and number of dendrites, rang- electrical synapse. ing in length from almost zero to many centimeters; (3) the length and size of the axon; and (4) the number of Although most synapses in the brain are chemical, presynaptic terminals, which may range from only a few electrical and chemical synapses may coexist and interact to as many as 200,000. These differences make neurons in the central nervous system. The bidirectional transmis- in various parts of the nervous system react differently to sion of electrical synapses permits them to help coordinate incoming synaptic signals and, therefore, perform many the activities of large groups of interconnected neurons. different functions. For example, electrical synapses are useful in detecting Presynaptic Terminals. Electron microscopic studies of the coincidence of simultaneous subthreshold depolar- the presynaptic terminals show that they have varied ana- izations within a group of interconnected neurons; this tomical forms, but most of them resemble small round or enables increased neuronal sensitivity and promotes syn- oval knobs and therefore are sometimes called terminal chronous firing of a group of interconnected neurons. knobs, boutons, end-feet, or synaptic knobs. “One-Way” Conduction at Chemical Synapses. Chem- Figure 46-5A illustrates the basic structure of a chemi- ical synapses have one exceedingly important character- cal synapse, showing a single presynaptic terminal on the 573 UNIT IX The Nervous System: A. General Principles and Sensory Physiology depolarizes the presynaptic membrane, these calcium channels open and allow large numbers of calcium ions to flow into the terminal (Figure 46-5A). The quantity of neurotransmitter that is then released from the terminal into the synaptic cleft is directly related to the number of calcium ions that enter (Video 46-2). The precise mecha- nism whereby the calcium ions cause this release is not known, but it is believed to be the following. Dendrites When the calcium ions enter the presynaptic termi- nal, they bind with special protein molecules on the inside surface of the presynaptic membrane, called release sites. This binding in turn causes the release sites to open Axon through the membrane, allowing a few transmitter ves- icles to release their transmitter into the cleft after each single action potential. For the vesicles that store the neu- Soma rotransmitter acetylcholine, between 2,000 and 10,000 molecules of acetylcholine are present in each vesicle, and there are enough vesicles in the presynaptic terminal to transmit from a few hundred to more than 10,000 action potentials.! Transmitter Actions on Postsynaptic Neurons—Function of Receptor Proteins The membrane of the postsynaptic neuron contains large numbers of receptor proteins, also shown in Figure 46- Figure 46-6. Typical anterior motor neuron showing presynaptic 5A. The molecules of these receptors have two important terminals on the neuronal soma and dendrites. Note also the single components: (1) a binding component that protrudes out- axon. ward from the membrane into the synaptic cleft, where it binds the neurotransmitter coming from the presynaptic membrane surface of a postsynaptic neuron. The presyn- terminal; and (2) an intracellular component that passes aptic terminal is separated from the postsynaptic neuro- all the way through the postsynaptic membrane to the nal soma by a synaptic cleft usually 200 to 300 angstroms interior of the postsynaptic neuron. (Å) wide. The terminal has two internal structures impor- Receptor activation controls the opening of ion chan- tant to the excitatory or inhibitory function of the syn- nels in the postsynaptic cell in one of two ways: (1) by gat- apse: the transmitter vesicles and the mitochondria. The ing ion channels directly and allowing passage of specified transmitter vesicles contain the neurotransmitter that types of ions through the membrane; or (2) by activating a when released into the synaptic cleft, excites or inhibits “second messenger” that is not an ion channel but, instead, the postsynaptic neuron. It excites the postsynaptic neu- is a molecule that protrudes into the cell cytoplasm and ron if the neuronal membrane contains excitatory recep- activates one or more substances inside the postsynaptic tors, and it inhibits the neuron if the membrane contains neuron. These second messengers increase or decrease inhibitory receptors. The mitochondria provide adenosine specific cellular functions. triphosphate (ATP), which in turn supplies the energy for Neurotransmitter receptors that directly gate ion synthesizing new transmitter substances. channels are often called ionotropic receptors, whereas When an action potential spreads over a presynaptic those that act through second messenger systems are terminal, depolarization of its membrane causes a small called metabotropic receptors. number of vesicles to empty into the cleft. The released transmitter in turn binds to a receptor on the postsynap- Ion Channels. The ion channels in the postsynaptic tic neuronal membrane, causing an immediate change in neuronal membrane are usually of two types: (1) cation its permeability characteristics and leading to excitation channels, which usually allow sodium ions to pass when or inhibition of the postsynaptic neuron, depending on opened but sometimes also allow potassium and/or cal- the neuronal receptor characteristics.! cium ions to pass; and (2) anion channels, which mainly allow chloride ions to pass but also allow minute quanti- Transmitter Release From Presynaptic ties of other anions to pass. As discussed in Chapter 4, Terminals—Role of Calcium Ions these ion channels are highly selective for transport of The membrane of the presynaptic terminal is called the one or more specific ions. This selectivity depends on its presynaptic membrane. It contains large numbers of diameter, shape, and the electrical charges and chemical voltage-gated calcium channels. When an action potential bonds along its inside surfaces. 574  Chapter 46 Organization of the Nervous System, Basic Functions of Synapses, and Neurotransmitters Transmitter substance Receptor Potassium Membrane protein channel enzyme UNIT IX ! " Opens channel # K+ 1 # 2 ATP GTP ! " GDP Activates G protein or GTP enzymes # cAMP cGMP GTP 4 3 GDP Activates gene Activates one or more transcription intracellular enzymes Proteins and Specific cellular structural changes chemical activators Figure 46-7. The second messenger system whereby a transmitter substance from an initial neuron can activate a second neuron by first caus- ing a transformational change in the receptor that releases the activated alpha (α) subunit of the G protein into the second neuron’s cytoplasm. Four subsequent possible effects of the G protein are shown, including the following: 1, opening an ion channel in the membrane of the second neuron; 2, activating an enzyme system in the neuron’s membrane; 3, activating an intracellular enzyme system; and/or 4, causing gene tran- scription in the second neuron. Return of the G protein to the inactive state occurs when guanosine triphosphate (GTP) bound to the α subunit is hydrolyzed to guanosine diphosphate (GDP), and the β and γ subunits are reattached to the α subunit. The cation channels that conduct sodium ions are “Second Messenger” System in the Postsynaptic lined with negative charges. These charges attract the Neuron. Many functions of the nervous system—for positively charged sodium ions into the channel when the example, the process of memory—require prolonged channel diameter increases to a size larger than that of changes in neurons for seconds to months after the ini- the hydrated sodium ion. However, these same negative tial transmitter substance is gone. The ion channels are charges repel chloride ions and other anions and prevent not suitable for causing prolonged postsynaptic neuronal their passage. changes because these channels close within milliseconds For the anion channels, when the channel diam- after the transmitter substance is no longer present. How- eters become large enough, chloride ions pass into the ever, in many cases, prolonged postsynaptic neuronal ex- channels and on through to the opposite side, whereas citation or inhibition is achieved by activating a second sodium, potassium, and calcium cations are blocked, messenger chemical system inside the postsynaptic neu- mainly because their hydrated ions are too large to ronal cell, and then it is the second messenger that causes pass. the prolonged effect. We will learn later that when cation channels open and There are several types of second messenger systems. allow positively charged sodium ions to enter, the positive One of the most common types uses a group of proteins electrical charges of the sodium ions will in turn excite called G proteins. Figure 46-7 shows a membrane recep- this neuron. Therefore, a neurotransmitter that opens tor G protein. The inactive G protein complex is free in cation channels is called an excitatory transmitter. Con- the cytosol and consists of guanosine diphosphate (GDP) versely, opening anion channels allows negative electrical plus three components: an alpha (α) component that is charges to enter, which inhibits the neuron. Therefore, the activator portion of the G protein, and beta (β) and neurotransmitters that open these channels are called gamma (γ) components that are attached to the alpha inhibitory transmitters. component. As long as the G protein complex is bound to When a neurotransmitter activates an ion channel, the GDP, it remains inactive. channel usually opens within a fraction of a millisecond; When the receptor is activated by a neurotransmit- when the transmitter substance is no longer present, the ter, following a nerve impulse, the receptor undergoes a channel closes equally rapidly. The opening and closing conformational change, exposing a binding site for the of ion channels provide a means for very rapid control of G protein complex, which then binds to the portion of postsynaptic neurons.! the receptor that protrudes into the interior of the cell. 575 UNIT IX The Nervous System: A. General Principles and Sensory Physiology This process permits the α subunit to release GDP and The different molecular and membrane mechanisms simultaneously bind guanosine triphosphate (GTP) while used by the different receptors to cause excitation or inhi- separating from the β and γ portions of the complex. The bition include the following. separated α-GTP complex is then free to move within the Excitation. cytoplasm of the cell and perform one or more of sev- 1. Opening of sodium channels to allow large numbers eral functions, depending on the specific characteristic of of positive electrical charges to flow to the interior of each type of neuron. The following four changes that can the postsynaptic cell. This action raises the intracel- occur are shown in Figure 46-7: lular membrane potential in the positive direction 1. Opening specific ion channels through the postsyn- up toward the threshold level for excitation. It is the aptic cell membrane. Shown in the upper right of most widely used means for causing excitation. the figure is a potassium channel that is opened in 2. Depressed conduction through chloride or potassium response to the G protein; this channel often stays channels or both. This action decreases the diffusion open for a prolonged time, in contrast to rapid clo- of negatively charged chloride ions to the inside of sure of directly activated ion channels that do not the postsynaptic neuron or decreases the diffusion use the second messenger system. of positively charged potassium ions to the outside. 2. Activation of cyclic adenosine monophosphate In either case, the effect is to make the internal (cAMP) or cyclic guanosine monophosphate (cGMP) membrane potential more positive than normal, in the neuronal cell. Recall that cAMP or cGMP can which is excitatory. activate highly specific metabolic machinery in the 3. Various changes in the internal metabolism of the neuron and, therefore, can initiate any one of many postsynaptic neuron to excite cell activity or, in some chemical results, including long-term changes in cases, to increase the number of excitatory mem- cell structure itself, which in turn alters long-term brane receptors or decrease the number of inhibi- excitability of the neuron. tory membrane receptors.! 3. Activation of one or more intracellular enzymes. The G protein can directly activate one or more intracel- Inhibition. lular enzymes. In turn, the enzymes can cause many 1. Opening of chloride ion channels through the post- specific chemical functions in the cell. synaptic neuronal membrane. This action allows 4. Activation of gene transcription. Activation of gene rapid diffusion of negatively charged chloride ions transcription is one of the most important effects of from outside the postsynaptic neuron to the inside, activation of the second messenger systems because thereby carrying negative charges inward and in- gene transcription can cause formation of new pro- creasing the negativity inside, which is inhibitory. teins within the neuron, thereby changing its meta- 2. Increase in conductance of potassium ions out of the bolic machinery or its structure. It is well known that neuron. This action allows positive ions to diffuse to structural changes of appropriately activated neurons the exterior, which causes increased negativity in- do occur, especially in long-term memory processes. side the neuron; this is inhibitory. Inactivation of the G protein occurs when the GTP 3. Activation of receptor enzymes. This inhibits cellular bound to the α subunit is hydrolyzed to GDP. This action metabolic functions and increases the number of causes the α subunit to release from its target protein, inhibitory synaptic receptors or decreases the num- thereby inactivating the second messenger systems, and ber of excitatory receptors.! then to combine again with the β and γ subunits, return- ing the G protein complex to its inactive state. CHEMICAL SUBSTANCES THAT FUNCTION It is clear that activation of second messenger sys- AS SYNAPTIC TRANSMITTERS tems within the neuron, whether of the G protein type or of other types, is extremely important for changing the More than 50 chemical substances have been proved or long-term response characteristics of different neuronal postulated to function as synaptic transmitters. Some of pathways. We will return to this subject in more detail them are listed in Tables 46-1 and 46-2, which provide in Chapter 58 when we discuss memory functions of the two groups of synaptic transmitters. One group com- nervous system.! prises small-molecule, rapidly acting transmitters. The other is made up of a large number of neuropeptides of Excitatory or Inhibitory Receptors in the much larger molecular size, which usually act much more Postsynaptic Membrane slowly. A few gaseous molecules, such as nitric oxide (NO), On activation, some postsynaptic receptors cause excita- hydrogen sulfide (H2S), and carbon monoxide (CO), may tion of postsynaptic neurons, and others cause inhibition. also serve as transmitter modulators, although their role The importance of having inhibitory and excitatory types as true neurotransmitters is still unclear. of receptors is that this feature gives an additional dimen- The small-molecule, rapidly acting transmitters cause sion to nervous function, allowing restraint of nervous most acute responses of the nervous system, such as action and excitation. transmission of sensory signals to the brain and motor 576  Chapter 46 Organization of the Nervous System, Basic Functions of Synapses, and Neurotransmitters Table 46-1 Small-Molecule, Rapidly Acting Transmitters Table 46-2 Neuropeptides, Slowly Acting Transmitters, or Growth Factors Class I Acetylcholine Hypothalamic-Releasing Hormones Class II: The Amines Thyrotropin-releasing hormone Norepinephrine Luteinizing hormone–releasing hormone UNIT IX Epinephrine Somatostatin (growth hormone inhibitory factor) Dopamine Serotonin Pituitary Peptides Melatonin Adrenocorticotropic hormone Histamine β-Endorphin Class III: Amino Acids α–Melanocyte-stimulating hormone Gamma-aminobutyric acid Glycine Prolactin Glutamate Luteinizing hormone Aspartate Thyrotropin Class IV Growth hormone ATP Arachidonic acid Vasopressin Nitric oxide Oxytocin Carbon monoxide Peptides That Act on Gut and Brain Leucine enkephalin Methionine enkephalin signals back to the muscles. The neuropeptides, in con- Substance P trast, usually cause more prolonged actions, such as Gastrin long-term changes in numbers of neuronal receptors, long-term opening or closure of certain ion channels, and Cholecystokinin possibly even long-term changes in numbers of synapses Vasoactive intestinal polypeptide or sizes of synapses. Nerve growth factor Brain-derived neurotropic factor Small-Molecule, Rapidly Acting Transmitters Neurotensin Insulin In most cases, the small-molecule types of transmitters are synthesized in the cytosol of the presynaptic termi- Glucagon nal and are absorbed via active transport into the many Peptides from Other Tissues transmitter vesicles in the terminal. Then, each time Angiotensin II an action potential reaches the presynaptic terminal, a Bradykinin few vesicles at a time release their transmitter into the Carnosine synaptic cleft. This action usually occurs within a mil- Sleep peptides lisecond or less by the mechanism described earlier. The Calcitonin subsequent action of the small-molecule transmitter on the membrane receptors of the postsynaptic neuron usually also occurs within another millisecond or less. transport proteins required for synthesizing and/or con- Most often, the effect is to increase or decrease conduc- centrating new transmitter substances inside the vesicle. tance through ion channels; an example is to increase Acetylcholine is a typical small-molecule transmitter sodium conductance, which causes excitation, or to that obeys the principles of synthesis and release, as stated increase potassium or chloride conductance, which earlier. This transmitter substance is synthesized in the causes inhibition. presynaptic terminal from acetyl coenzyme A and choline in the presence of the enzyme choline acetyltransferase. Recycling of Small-Molecule Types of Vesicles. Vesi- It is then transported into its specific vesicles. When the cles that store and release small-molecule transmitters are vesicles later release acetylcholine into the synaptic cleft continually recycled and used over and over again. After during synaptic neuronal signal transmission, the acetyl- they fuse with the synaptic membrane and open to release choline is rapidly split again to acetate and choline by the their transmitters, the vesicle membrane at first simply enzyme cholinesterase, which is present in the proteo- becomes part of the synaptic membrane. However, within glycan reticulum that fills the space of the synaptic cleft. seconds to minutes, the vesicle portion of the membrane Then, once again, inside the presynaptic terminal, the invaginates back to the inside of the presynaptic terminal vesicles are recycled, and choline is actively transported and pinches off to form a new vesicle. The new vesicular back into the terminal to be used again for synthesis of new membrane still contains appropriate enzyme proteins or acetylcholine.! 577 UNIT IX The Nervous System: A. General Principles and Sensory Physiology Characteristics of Some Important Small-Molecule mechanism of formation in the presynaptic terminal and Transmitters. Acetylcholine is secreted by neurons in in its actions on the postsynaptic neuron. It is not pre- many areas of the nervous system but specifically by (1) formed and stored in vesicles in the presynaptic terminal, the terminals of the large pyramidal cells from the mo- as are other transmitters. Instead, it is synthesized almost tor cortex; (2) several different types of neurons in the instantly as needed and then diffuses out of the presynap- basal ganglia; (3) motor neurons that innervate the skel- tic terminals over a period of seconds rather than being etal muscles; (4) preganglionic neurons of the autonomic released in vesicular packets. Next, it diffuses into post- nervous system; (5) postganglionic neurons of the para- synaptic neurons nearby. In the postsynaptic neuron, it sympathetic nervous system; and (6) some of the post- usually does not alter the membrane potential greatly but ganglionic neurons of the sympathetic nervous system. In instead changes intracellular metabolic functions that most cases, acetylcholine has an excitatory effect; how- modify neuronal excitability for seconds, minutes, or per- ever, it is known to have inhibitory effects at some periph- haps even longer.! eral parasympathetic nerve endings, such as inhibition of the heart by the vagus nerves. Neuropeptides Norepinephrine is secreted by the terminals of many Neuropeptides are synthesized differently and have neurons whose cell bodies are located in the brain stem actions that are usually slow and in other ways differ- and hypothalamus. Specifically, norepinephrine-secreting ent from those of the small-molecule transmitters. The neurons located in the locus ceruleus in the pons send neuropeptides are not synthesized in the cytosol of the nerve fibers to widespread areas of the brain to help presynaptic terminals. Instead, they are synthesized as control overall activity and mood of the mind, such as integral parts of large-protein molecules by ribosomes in increasing the level of wakefulness. In most of these areas, the neuronal cell body. norepinephrine probably activates excitatory receptors, The protein molecules then enter the spaces inside the but in a few areas, it activates inhibitory receptors instead. endoplasmic reticulum of the cell body and subsequently Norepinephrine is also secreted by most postganglionic inside the Golgi apparatus, where two changes occur. neurons of the sympathetic nervous system, where it First, the neuropeptide-forming protein is enzymatically excites some organs but inhibits others. split into smaller fragments, some of which are either the Dopamine is secreted by neurons that originate in neuropeptide itself or a precursor of it. Second, the Golgi the substantia nigra. The termination of these neurons is apparatus packages the neuropeptide into minute trans- mainly in the striatal region of the basal ganglia. The effect mitter vesicles that are released into the cytoplasm. Then, of dopamine is usually inhibition. the transmitter vesicles are transported all the way to the Glycine is secreted mainly at synapses in the spinal cord. tips of the nerve fibers by axonal streaming of the axon It is believed to always act as an inhibitory transmitter. cytoplasm, traveling at the slow rate of only a few centi- Gamma-aminobutyric acid (GABA) is secreted by meters per day. Finally, these vesicles release their trans- nerve terminals in the spinal cord, cerebellum, basal gan- mitter at the neuronal terminals in response to action glia, and many areas of the cortex. It is the primary inhibi- potentials in the same manner as for small-molecule tory neurotransmitter in the adult central nervous system. transmitters. However, the vesicle is autolyzed and is not Yet, in the early stages of brain development, including the reused. embryonic period and first week of postnatal life, GABA Because of this laborious method of forming the neu- is thought to serve as an excitatory neurotransmitter. ropeptides, much smaller quantities of neuropeptides Glutamate is secreted by the presynaptic terminals in than the small-molecule transmitters are usually released. many of the sensory pathways entering the central ner- This difference is partly compensated for by the fact that vous system, as well as in many areas of the cerebral cor- the neuropeptides are generally a thousand or more times tex. It probably always causes excitation. as potent as the small-molecule transmitters. Another Serotonin is secreted by nuclei that originate in the important characteristic of the neuropeptides is that they median raphe of the brain stem and project to many brain often cause much more prolonged actions. Some of these and spinal cord areas, especially to the dorsal horns of the actions include prolonged closure of calcium channels, spinal cord and the hypothalamus. Serotonin acts as an prolonged changes in the metabolic machinery of cells, inhibitor of pain pathways in the cord; an inhibitor action prolonged changes in activation or deactivation of spe- in the higher regions of the nervous system is believed cific genes in the cell nucleus, and/or prolonged altera- to help control the mood of the person, perhaps even to tions in numbers of excitatory or inhibitory receptors. cause sleep. Some of these effects last for days, but others last perhaps Nitric oxide is produced by nerve terminals in areas for months or years. Our knowledge of the functions of of the brain responsible for long-term behavior and the neuropeptides is only beginning to develop. memory. Therefore, this gaseous transmitter might in Neuropeptide and Small-Molecule Transmitters May the future explain some behavior and memory functions Coexist in the Same Neurons. Slowly acting neuro- that thus far have defied understanding. Nitric oxide is peptide transmitters and rapidly acting, small-molecule different from other small-molecule transmitters in its 578  Chapter 46 Organization of the Nervous System, Basic Functions of Synapses, and Neurotransmitters A Co-release synaptic vesicles of the same neuron and contribute to co- Action transmission of signals to a postsynaptic neuron. Moreo- potential ver, their release may be differentially regulated because of different calcium ion sensitivities (Figure 46-8B) or spatial segregation of the vesicles on different boutons Ca2+ Ca2+ (Figure 46-8C). UNIT IX The co-release of transmitters and co-transmission of signals obviously has important functional implications. Each different transmitter released from the same pre- synaptic neuron has its own specific receptors and may have inhibitory or excitatory influences on the postsyn- aptic target. Different neurons may release different com- binations of fast-acting transmitters that directly activate B Co-transmission; differential Ca2+ sensitivity postsynaptic receptors, as well as slow-acting transmit- ters that require activation of second messenger cascades Single Multiple and postsynaptic changes in gene expression. action action potential potentials An example of co-release of two small molecule trans- mitters is found in the raphe nucleus, located in the brain stem. These neurons provide innervation to several brain Ca2+ Ca2+ regions, they can co-release serotonin and glutamate, and they play an important role in the cycle of sleeping and wakefulness (see Chapters 59 and 60).! ELECTRICAL EVENTS DURING NEURONAL EXCITATION The electrical events in neuronal excitation have been studied especially in the large motor neurons of the C Co-transmission; Spatial segregation anterior horns of the spinal cord. Therefore, the events described in the next few sections pertain essentially to these neurons. Except for quantitative differences, they Action also apply to most other neurons of the nervous system. potential Ca2+ Ca2+ Resting Membrane Potential of the Neuronal Soma. Figure 46-9 shows the soma of a spinal motor neuron, in- dicating a resting membrane potential of about −65 milli- volts (mV). This resting membrane potential is somewhat less negative than that found in large peripheral nerve fibers and in skeletal muscle fibers; the lower voltage is Figure 46-8. Co-release of neurotransmitters and co-transmission of important because it allows both positive and negative neuronal signals. A, With co-release, both transmitters (green and control of the degree of excitability of the neuron. That purple) are stored in the same set of synaptic vesicles and released to- is, decreasing the voltage to a less negative value makes gether when an action potential reaches the presynaptic terminal. B, the membrane of the neuron more excitable, whereas in- With co-transmission, the transmitters are stored in different popula- tions of synaptic vesicles with differential release mediated by differ- creasing this voltage to a more negative value makes the ent calcium ion (Ca2+) sensitivities; a single action potential might neuron less excitable. This mechanism is the basis for the release one set of vesicles (green), whereas multiple action potentials two modes of function of the neuron—either excitation might be required to release both sets of vesicles (green and purple). or inhibition—as explained in the next sections.! C, Co-transmission can also rely on the spatial segregation of vesicle populations to different boutons, allowing uniform information to be transmitted to different postsynaptic targets. Concentration Differences of Ions Across the Neuronal Somal Membrane. Figure 46-9 also shows the concentration differences across the neuronal somal transmitters are often stored and released from the same membrane of the three ions that are most important neurons. In some cases, two or more of these transmit- for neuronal function—sodium ions, potassium ions, ters are co-localized in the same synaptic vesicles and and chloride ions. At the top of this figure, the sodium are co-released when an action potential reaches the pr- ion concentration is shown to be high in the extracellular esynaptic terminal (Figure 46-8A). In other cases, these fluid (142 mEq/L) but low inside the neuron (14 mEq/L). transmitters may be localized in different populations of This sodium concentration gradient is caused by a strong 579 UNIT IX The Nervous System: A. General Principles and Sensory Physiology Dendrite calculates to be +61 mV. However, the actual membrane potential is −65 mV, not +61 mV. Therefore, the sodium ions that leak to the interior are immediately pumped back to the exterior by the sodium pump, thus maintain- ing the −65-mV negative potential inside the neuron. Na+: 142 mEq/L 14 mEq/L For potassium ions, the concentration gradient is 120 (Pumps) mEq/L inside the neuron and 4.5 mEq/L outside. This K+: 4.5 mEq/L 120 mEq/L !65 Axon concentration gradient calculates to be a Nernst potential mV of −86 mV inside the neuron, which is more negative than Cl-: 107 mEq/L ? 8 mEq/L the −65 that actually exists. Therefore, because of the high Pump intracellular potassium ion concentration, there is a net tendency for potassium ions to diffuse to the outside of Axon hillock the neuron, but this action is opposed by continual pump- ing of these potassium ions back to the interior. Finally, the chloride ion gradient, 107 mEq/L outside Figure 46-9. Distribution of sodium, potassium, and chloride ions and 8 mEq/L inside, yields a Nernst potential of −70 mV across the neuronal somal membrane; origin of the intrasomal mem- inside the neuron, which is only slightly more negative brane potential. than the actual measured value of −65 mV. Therefore, chloride ions tend to leak very slightly to the interior of somal membrane sodium pump that continually pumps the neuron, but those few that do leak are moved back to sodium out of the neuron. the exterior, perhaps by an active chloride pump. Figure 46-9 also shows that potassium ion concentra- Keep these three Nernst potentials in mind, and tion is high inside the neuronal soma (120 mEq/L) but remember the direction in which the different ions tend low in the extracellular fluid (4.5 mEq/L). Furthermore, to diffuse, because this information is important in under- it shows that there is a potassium pump (the other half of standing both excitation and inhibition of the neuron by the Na+-K+ pump) that pumps potassium to the interior. synapse activation or inactivation of ion channels.! Figure 46-9 depicts the chloride ion to be of high con- Uniform Distribution of Electrical Potential Inside the centration in the extracellular fluid but of low concentra- Neuronal Soma. The interior of the neuronal soma con- tion inside the neuron. The membrane may be somewhat tains a highly conductive electrolytic solution, the intra- permeable to chloride ions, and there may be a weak cellular fluid of the neuron. Furthermore, the diameter of chloride pump. Yet, most of the reason for the low con- the neuronal soma is large (from 10 to 80 micrometers), centration of chloride ions inside the neuron is the −65 causing almost no resistance to conduction of electric mV in the neuron. That is, this negative voltage repels the current from one part of the somal interior to another negatively charged chloride ions, forcing them outward part. Therefore, any change in potential in any part of the through channels until the concentration is much less intrasomal fluid causes an almost exactly equal change in inside the membrane than outside. potential at all other points inside the soma, as long as the Let us recall from Chapters 4 and 5 that an electrical neuron is not transmitting an action potential. This prin- potential across the cell membrane can oppose move- ciple is important because it plays a major role in “summa- ment of ions through a membrane if the potential is of tion” of signals entering the neuron from multiple sources, proper polarity and magnitude. A potential that exactly as we shall see in subsequent sections of this chapter.! opposes movement of an ion is called the Nernst potential for that ion, represented by the following equation: Effect of Synaptic Excitation on the Postsynaptic Membrane—Excitatory Postsynaptic Potential. Fig- ⎛ Concentration inside ⎞ ure 46-10A shows the resting neuron with an unexcited EMF (mV ) = ±61 × log ⎜ ⎝ Concentration outside ⎠⎟ presynaptic terminal resting on its surface. The resting membrane potential everywhere in the soma is −65 mV. where EMF (electromotive force) is the Nernst potential Figure 46-10B shows a presynaptic terminal that has in millivolts on the inside of the membrane. The potential secreted an excitatory transmitter into the cleft between will be negative (−) for positive ions and positive (+) for the terminal and neuronal somal membrane. This trans- negative ions. mitter acts on the membrane excitatory receptor to Now let us calculate the Nernst potential that will increase the membrane’s permeability to Na+. Because of exactly oppose the movement of each of the three sepa- the large sodium concentration gradient and large electri- rate ions—sodium, potassium, and chloride. cal negativity inside the neuron, sodium ions diffuse rap- For the sodium concentration difference shown in Fig- idly to the inside of the membrane. ure 46-9 (142 mEq/L on the exterior and 14 mEq/L on the The rapid influx of positively charged sodium ions to interior), the membrane potential that will exactly oppose the interior neutralizes part of the negativity of the resting sodium ion movement through the sodium channels membrane potential. Thus, in Figure 46-10B, the resting 580  Chapter 46 Organization of the Nervous System, Basic Functions of Synapses, and Neurotransmitters A main reason for this point of origin of the action potential is that the soma has relatively few voltage-gated sodium channels in its membrane, which makes it difficult for the !65 mV EPSP to open the required number of sodium channels to elicit an action potential. Conversely, the membrane of the UNIT IX initial segment has seven times as great a concentration Resting neuron of voltage-gated sodium channels as the soma and, there- fore, can generate an action potential with much greater B Initial segment of axon ease than can the soma. The EPSP that will elicit an ac- Excitatory tion potential in the axon initial segment is between +10 and +20 mV, in contrast to the +30 or +40 mV or more !45 mV required on the soma. Once the action potential begins, it travels peripherally Na+ along the axon and usually also backward over the soma. influx In some cases, it travels backward into the dendrites but Excited neuron Spread of action potential not into all of them because they, like the neuronal soma, C have very few voltage-gated sodium channels and there- Cl! influx fore frequently cannot generate action potentials at all. Inhibitory Thus, in Figure 46-10B, the threshold for excitation of the !70 mV neuron is shown to be about −45 mV, which represents an EPSP of +20 mV—that is, 20 mV more positive than the normal resting neuronal potential of −65 mV.! K+ efflux Inhibited neuron ELECTRICAL EVENTS DURING NEURONAL Figure 46-10. Three states of a neuron. A, Resting neuron, with a normal intraneuronal potential of −65 mV. B, Neuron in an excited INHIBITION state, with a less negative intraneuronal potential (−45 mV) caused by Effect of Inhibitory Synapses on the Postsynaptic sodium influx. C, Neuron in an inhibited state, with a more negative Membrane—Inhibitory Postsynaptic Potential. The intraneuronal membrane potential (−70 mV) caused by potassium ion efflux, chloride ion influx, or both. inhibitory synapses mainly open chloride channels, allow- ing for easier passage of chloride ions. To understand how the inhibitory synapses inhibit the postsynaptic neuron, membrane potential has increased in the positive direc- we must recall what we learned about the Nernst poten- tion from −65 to −45 mV. This positive increase in voltage tial for chloride ions. We calculated the Nernst potential above the normal resting neuronal potential—that is, to for chloride ions to be about −70 mV. This potential is a less negative value—is called the excitatory postsynap- more negative than the −65 mV normally present inside tic potential (EPSP), because if this potential rises high the resting neuronal membrane. Therefore, opening the enough in the positive direction, it will elicit an action chloride channels will allow negatively charged chloride potential in the postsynaptic neuron, thus exciting it. (In ions to move from the extracellular fluid to the interior, this case, the EPSP is +20 mV—i.e., 20 mV more positive which will make the interior membrane potential more than the resting value.) negative than normal, approaching the −70 mV level. Discharge of a single presynaptic terminal can never Opening potassium channels will allow positively increase the neuronal potential from −65 mV all the way charged potassium ions to move to the exterior and will up to −45 mV. An increase of this magnitude requires also make the interior membrane potential more nega- simultaneous discharge of many terminals—about 40 tive than usual. Thus, both chloride influx and potas- to 80 for the usual anterior motor neuron—at the same sium e%ux increase the degree of intracellular negativity, time or in rapid succession. This simultaneous discharge called hyperpolarization. The neuron is inhibited because occurs by a process called summation, discussed in the the membrane potential is even more negative than the next sections.! normal intracellular potential. Therefore, an increase in negativity beyond the normal resting membrane potential Generation of Action Potentials in the Initial Segment level is called an inhibitory postsynaptic potential (IPSP). of the Axon Leaving the Neuron—Threshold for Figure 46-10C shows the effect on the membrane Excitation. When the EPSP rises high enough in the potential caused by activation of inhibitory synapses, positive direction, there comes a point at which this rise allowing chloride influx into the cell and/or potas- initiates an action potential in the neuron. However, the sium e%ux out of the cell, with the membrane potential action potential does not begin adjacent to the excita- decreasing from its normal value of −65 mV to the more tory synapses. Instead, it begins in the initial segment of negative value of −70 mV. This membrane potential is 5 the axon where the axon leaves the neuronal soma. The mV more negative than normal and is therefore an IPSP 581 UNIT IX The Nervous System: A. General Principles and Sensory Physiology of −5 mV, which inhibits transmission of the nerve signal Precisely the opposite effect occurs for an IPSP. That is, the through the synapse.! inhibitory synapse increases the permeability of the mem- brane to potassium or chloride ions, or both, for 1 to 2 milli- Presynaptic Inhibition seconds, and this action decreases the intraneuronal potential In addition to postsynaptic inhibition caused by inhibitory to a more negative value than normal, thereby creating the synapses operating at the neuronal membrane, presynap- IPSP. This potential also dies away in about 15 milliseconds. tic inhibition often occurs at the presynaptic terminals Other types of transmitter substances can excite or before the signal ever reaches the synapse. inhibit the postsynaptic neuron for much longer peri- Presynaptic inhibition is caused by release of an inhibi- ods—for hundreds of milliseconds or even for seconds, tory substance onto the outsides of the presynaptic nerve minutes, or hours. This is especially true for some of the fibrils before their own endings terminate on the post- neuropeptide transmitters.! synaptic neuron. In most cases, the inhibitory transmitter substance is GABA, which opens anion channels, allowing “Spatial Summation” in Neurons— large numbers of chloride ions to diffuse into the terminal Threshold for Firing fibril. The negative charges of these ions inhibit synaptic Excitation of a single presynaptic terminal on the surface of transmission because they cancel much of the excitatory a neuron almost never excites the neuron. The amount of effect of the positively charged sodium ions that also enter transmitter released by a single terminal to cause an EPSP the terminal fibrils when an action potential arrives. is usually no more than 0.5 to 1 mV instead of the 10 to Presynaptic inhibition occurs in many of the sensory 20 mV normally required to reach threshold for excitation. pathways in the nervous system. In fact, adjacent sensory However, many presynaptic terminals are usually stim- nerve fibers often mutually inhibit one another, which ulated at the same time. Even though these terminals are minimizes sideways spread and mixing of signals in sen- spread over wide areas of the neuron, their effects can sory tracts. We discuss the importance of this phenom- still summate; that is, they can add to one another until enon more fully in subsequent chapters.! neuronal excitation occurs. We pointed out earlier that a change in potential at any single point within the soma Time Course of Postsynaptic Potentials will cause the potential to change almost equally every- When an excitatory synapse excites the anterior motor where inside the soma. Therefore, for each excitatory syn- neuron, the neuronal membrane becomes highly perme- apse that discharges simultaneously, the total intrasomal able to sodium ions for 1 to 2 milliseconds. During this potential becomes more positive by 0.5 to 1.0 mV. When short time, enough sodium ions diffuse to the interior of the EPSP becomes great enough, the threshold for firing the postsynaptic motor neuron to increase its intraneu- will be reached, and an action potential will develop spon- ronal potential by a few millivolts, thus creating the EPSP taneously in the initial segment of the axon, as shown in shown by the blue and green curves of Figure 46-11. Figure 46-11. The bottom postsynaptic potential in the This potential then slowly declines over the next 15 mil- figure was caused by simultaneous stimulation of 4 syn- liseconds because this is the time required for the excess apses; the next higher potential was caused by stimula- positive charges to leak out of the excited neuron and re- tion of 8 synapses; finally, a still higher EPSP was caused establish the normal resting membrane potential. by stimulation of 16 synapses. In this last case, the firing threshold had been reached, and an action potential was generated in the axon. 16 16 synapses firing This effect of summing simultaneous postsynaptic +20 potentials by activating multiple terminals on widely Action potential 8 8 synapses firing spaced areas of the neuronal membrane is called spatial 0 4 4 synapses firing summation.! –20 “Temporal Summation” Caused by Millivolts 16 Successive Discharges of a Presynaptic –40 Excitatory postsynaptic Terminal potential 8 Each time a presynaptic terminal fires, the released trans- –60 4 mitter substance opens the membrane channels for at Resting membrane potential most 1 or 2 milliseconds. However, the changed postsyn- –80 aptic potential lasts up to 15 milliseconds after the syn- 0 2 4 6 8 10 12 14 16 aptic membrane channels have already closed. Therefore, Milliseconds a second opening of the same channels can increase the Figure 46-11. Excitatory postsynaptic potentials. This shows that postsynaptic potential to a still greater level, and the more simultaneous firing of only a few synapses will not cause sufficient summated potential to elicit an action potential but that simultane- rapid the rate of stimulation, the greater the postsynap- ous firing of many synapses will raise the summated potential to tic potential becomes. Thus, successive discharges from a threshold for excitation and cause a superimposed action potential. single presynaptic terminal, if they occur rapidly enough, 582  Chapter 46 Organization of the Nervous System, Basic Functions of Synapses, and Neurotransmitters can add to one another; that is, they can summate. This Decrement of Electrotonic Conduction in the type of summation is called temporal summation. Dendrites—Greater Excitatory (or Inhibitory) Effect by Synapses Located Near the Soma. In Figure 46-12, Simultaneous Summation of Inhibitory and multiple excitatory and inhibitory synapses are shown Excitatory Postsynaptic Potentials. If an IPSP tends stimulating the dendrites of a neuron. On the two den- UNIT IX to decrease the membrane potential to a more negative drites to the left, there are excitatory effects near the tip value while an EPSP tends to increase the potential at