Loewi’s successful heartbeat experiment, diagrammed in Experiment 5-1, marked the beginning of research into how chemicals carry information from one neuron to another in the nervous system. Loewi was the first to isolate a chemical messenger. We now know that chemical as acetylcholine (ACh), the same transmitter that activates skeletal muscles, as described in Section 4-4. Yet here, ACh acts to inhibit heartbeat, to slow it down. It turns out that ACh activates skeletal muscles in the somatic nervous system and may either excite or inhibit various internal organs in the autonomic system. And, yes, acetylcholine is the chemical messenger that slows the heart in diving bradycardia.

In further experiments modeled on his procedure in Experiment 5-1, Loewi stimulated another nerve to the heart, the accelerator nerve, and heart rate increased. The fluid that bathed the accelerated heart also speeded the beat of a second heart that was not electrically stimulated. Loewi identified the chemical that carries the message to speed up heart rate in frogs as epinephrine (EP; epi-, above; nephron, kidney), also known as adrenaline. Adrenaline (Latin) and epinephrine (Greek) are the same substance, produced by the adrenal glands located atop the kidneys. Adrenaline is the name more people know, in part because a drug company used it as a trade name, but epinephrine is common parlance in the science community.

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Further experimentation eventually demonstrated that in mammals, the chemical that accelerates heart rate is norepinephrine (NE; also noradrenaline), a chemical closely related to EP. The results of Loewi’s complementary experiments showed that acetylcholine from the vagus nerve inhibits heartbeat, and epinephrine from the accelerator nerve excites it.

Chemical messengers released by a neuron onto a target to cause an excitatory or inhibitory effect are neurotransmitters. Outside the central nervous system, many of the same chemicals, epinephrine among them, circulate in the bloodstream as hormones. Under control of the hypothalamus, the pituitary gland releases hormones into the bloodstream to excite or inhibit targets such as the organs and glands in the autonomic and enteric nervous systems. In part because hormones travel throughout the body to distant targets, their action is slower than that of CNS neurotransmitters prodded by the lightning-quick nerve impulse. But the real difference between neurotransmitters and hormones is the distances they travel before they encounter their receptors.

Loewi’s discoveries led to the search for more neurotransmitters and their functions. The actual number of transmitters is an open question, with 100 posited as the maximum. The confirmed number is 60. Whether a chemical is accepted as a neurotransmitter depends on the extent to which it meets certain criteria. As this chapter unfolds, you will learn those criteria along with the names and functions of many neurotransmitters. You will also learn how groups of neurons form neurotransmitter systems throughout the brain to modulate, or temper, aspects of behavior. The three Clinical Focus boxes in this chapter tell the fascinating story of how one such neurotransmitter system has yielded deep insight into brain function. When depleted in a particular brain area, this neurotransmitter is associated with a specific neurological disorder. The story begins with Clinical Focus 5-2, Parkinson Disease.

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Loewi’s discovery about the chemical messengers that regulate heart rate was the first of two seminal findings that form the foundation for current understanding of how neurons communicate. The second had to wait nearly 30 years, for the invention of the electron microscope. Shown at the right in Figure 5-1, it enables scientists to see the structure of a synapse.

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The electron microscope uses some principles of a light microscope, shown at the left in Figure 5-1, and an oscilloscope. The light microscope illuminates the tissue and magnifies the image. The electron microscope projects a beam of electrons through a very thin slice of tissue. The tissue’s varying structures scatter the electron beam onto a reflective surface, where they leave an image, or shadow, of the tissue. Electron waves are smaller than light waves and scatter much less when the beam strikes tissue, allowing for much higher resolution.

To see how much finer an electron microscope’s resolution is relative to that of a light microscope, compare the images at the bottom of Figure 5-1. An electron microscope’s resolution can be much higher than a light microscope because electron waves are smaller than light waves, so much less scatter attends the beam striking the tissue. When tissue is stained with a substance that reflects electrons, vanishingly fine structural details emerge.

Chemical Synapses

The first good electron micrographs, made in the 1950s, revealed synaptic structure for the first time. In the center of the micrograph in Figure 5-2A, the upper part of the synapse is the axon terminal, or end foot; the lower part is the receiving dendrite. The round granular substances in the terminal are the synaptic vesicles, containing neurotransmitter.

Dark patches on the axon terminal membrane are proteins that serve largely as ion channels to signal the release of the transmitters or as pumps to recapture the transmitter after its release. The dark patches on the dendrite consist mainly of receptor molecules also made up of proteins that receive chemical messages. The terminal and the dendrite are separated by a small space, the synaptic cleft. The synaptic cleft is central to synapse function, because neurotransmitter chemicals must bridge this gap to carry a message from one neuron to the next.

You can also see in the micrograph that the synapse is sandwiched by many surrounding structures, including glial cells, other axons and dendritic processes, and other synapses. The surrounding glia contribute to chemical neurotransmission in several ways—by supplying the building blocks for neurotransmitter synthesis, by confining the movement of neurotransmitters to the synapse, and by mopping up excess neurotransmitter molecules, for example.

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Figure 5-2B details the process of neurotransmission at a chemical synapse, the junction where messenger molecules are released from one neuron to interact with the next neuron. Here the presynaptic membrane forms the axon terminal, the postsynaptic membrane forms the dendritic spine, and the space between the two is the synaptic cleft. Within the axon terminal are specialized structures, including mitochondria, the organelles that supply the cell’s energy needs; storage granules, large compartments that hold several synaptic vesicles; and microtubules, which transport substances, including neurotransmitter, to the terminal.

Electrical Synapses

Chemical synapses are the rule in mammalian nervous systems, but they are not the only kind of synapse. Some neurons influence each other electrically through a gap junction, or electrical synapse, where the cell membranes of two neurons come into direct contact (Figure 5-3). Ion channels in one cell membrane connect to ion channels in the other membrane, forming a pore that allows ions to pass from one neuron to the other in both directions.

This fusion eliminates the brief delay in information flow—about 5 milliseconds per synapse—of chemical transmission (compare Figure 5-3 with Figure 5-2B). For example, the crayfish’s gap junctions activate its tail flick, a response that provides quick escape from a predator. Gap junctions are found in the mammalian brain, where in some regions they allow groups of interneurons to synchronize their firing rhythmically. Gap junctions also allow glial cells and neurons to exchange substances (Dere & Zlomuzica, 2012).

Why, if chemical synapses transmit messages more slowly, do mammals rely on them more than on gap junctions? The answer is that chemical synapses flexibly control whether a message is passed from one neuron to the next; they can amplify or diminish a signal sent from one neuron to the next; and they can change with experience to alter their signals and so mediate learning.

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The four-step process of transmitting information across a chemical synapse is illustrated in Figure 5-4. In brief, the neurotransmitter must be

Step 1: Neurotransmitter Synthesis and Storage

Neurotransmitters are derived in two general ways, and these origins define two broad classes of neurotransmitters. Some are synthesized in the cell body according to instructions in the neuron’s DNA, packaged in membranes on the Golgi bodies, and transported on microtubules to the axon terminal. Cell-derived neurotransmitters may also be manufactured within the presynaptic terminal from mRNA transported to the terminal.

Other neurotransmitters are synthesized in the axon terminal from building blocks derived from food. Transporters, protein molecules that pump substances across the cell membrane, absorb the required precursor chemicals from the blood supply. (Sometimes transporter proteins absorb the neurotransmitter ready-made.) Mitochondria in the axon terminal provide the energy needed both to synthesize precursor chemicals into the neurotransmitter and to wrap them in membranous vesicles.

Regardless of their origin, neurotransmitters in the axon terminal can usually be found in three locations, depending on their type. Some vesicles are warehoused in granules, some are attached to microfilaments (a type of microtubule; see Figure 5-2B) in the terminal, and still others are attached to the presynaptic membrane. These sites are the steps by which a transmitter is transported from a granule to the membrane, ready to be released into the synaptic cleft.

Step 2: Neurotransmitter Release

Synaptic vesicles loaded with neurotransmitters must dock near release sites on the presynaptic membrane. Then the vesicles are primed to prepare them to fuse rapidly in response to calcium (Ca²⁺) influx. When an action potential reaches the presynaptic membrane, voltage changes on the membrane set the release process in motion. Calcium cations play a critical role. The presynaptic membrane is rich in voltage-sensitive calcium channels, and the surrounding extracellular fluid is rich in Ca²⁺. As illustrated in Figure 5-5, the action potential’s arrival opens these calcium channels, allowing an influx of calcium ions into the axon terminal.

Primed vesicles fuse with the presynaptic membrane quickly in response to the calcium influx and empty their contents into the synaptic cleft by exocytosis. The vesicles from storage granules and on filaments then move up to replace the vesicles that just emptied their contents.

Step 3: Receptor-Site Activation

After its release from vesicles on the presynaptic membrane, the neurotransmitter diffuses across the synaptic cleft and binds to specialized protein molecules embedded in the postsynaptic membrane. These transmitter-activated receptors have binding sites for the transmitter, which we elaborate on in Section 5-3. Depending on the properties of receptors on the postsynaptic membrane, the postsynaptic cell may be affected in one of three ways. The receptor and its associated ion channel or intracellular messenger system may

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In addition to interacting with the postsynaptic membrane’s receptors, a neurotransmitter may interact with receptors on the presynaptic membrane: it may influence the cell that just released it. That is, a neurotransmitter may activate presynaptic receptors called autoreceptors (self-receptors) to receive messages from their own axon terminals.

How much neurotransmitter is needed to send a message? Bernard Katz was awarded a Nobel Prize in 1970 for providing an answer. Recording electrical activity from the postsynaptic membranes of muscles, he detected small, spontaneous depolarizations now called miniature postsynaptic potentials. The potentials varied in size, but each size appeared to be a multiple of the smallest potential.

Katz concluded that the smallest postsynaptic potential is produced by the release of the contents of just one synaptic vesicle. This amount of neurotransmitter is called a quantum. To produce a postsynaptic potential large enough to initiate a postsynaptic action potential requires the simultaneous release of many quanta from the presynaptic cell.

The results of subsequent experiments show that the number of quanta released from the presynaptic membrane in response to a single action potential depends on two factors: (1) the amount of Ca²⁺ that enters the axon terminal in response to the action potential and (2) the number of vesicles docked at the membrane, waiting to be released. Both factors are relevant to synaptic activity during learning, which we consider in Section 5-4.

Step 4: Neurotransmitter Deactivation

Chemical transmission would not be an effective messenger system if a neurotransmitter lingered within the synaptic cleft, continuing to occupy and stimulate receptors. If this happened, the postsynaptic cell could not respond to other messages sent by the presynaptic neuron. Thus, after a neurotransmitter has done its work, it is quickly removed from receptor sites and from the synaptic cleft. Deactivation is accomplished in at least four ways:

Highlighting the flexibility of synaptic function, an axon terminal has chemical mechanisms that enable it to respond to the frequency of its own use. If the terminal is very active, the amount of neurotransmitter made and stored there increases. If the terminal is not often used, however, enzymes within the terminal buttons may break down excess transmitter. The by-products are then reused or excreted from the neuron. Axon terminals may even send messages to the neuron’s cell body requesting increased supplies of the neurotransmitter or the molecules with which to make it.

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So far we have considered a generic chemical synapse, with features possessed by most synapses. Synapses vary widely in the nervous system. Each type is specialized in location, structure, function, and target. Figure 5-6 illustrates this diversity on a single hypothetical neuron.

You have already encountered two kinds of synapses. One is the axomuscular synapse, in which an axon synapses with a muscle end plate, releasing acetylcholine. The other synapse familiar to you is the axodendritic synapse, detailed in Figure 5-2B, in which the axon terminal of a neuron synapses with a dendrite or dendritic spine of another neuron.

Figure 5-6 diagrams axon terminals at the axodendritic synapse as well as the axosomatic synapse, at a cell body; the axoaxonic synapse, on another axon; and the axosynaptic synapse, on another presynaptic terminal—that is, at the synapse between some other axon and its target. Axoextracellular synapses have no specific targets but instead secrete their transmitter chemicals into the extracellular fluid. In the axosecretory synapse, a terminal synapses with a tiny blood vessel, a capillary, and secretes its transmitter directly into the blood. Finally, synapses are not limited to axon terminals. Dendrites also may send messages to other dendrites through dendrodendritic synapses.

This wide variety of connections makes the synapse a versatile chemical delivery system. Synapses can deliver transmitters to highly specific sites or diffuse locales. Through connections to the dendrites, cell body, or axon of a neuron, transmitters can control the neuron’s actions in different ways.

Through axosynaptic connections, they can also exert exquisite control over another neuron’s input to a cell. By excreting transmitters into extracellular fluid or into the blood, axoextracellular and axosecretory synapses can modulate the function of large areas of tissue or even the entire body. Many transmitters secreted by neurons act as hormones circulating in your blood, with widespread influences on your body.

Gap junctions, shown in Figure 5-3, further increase the signaling diversity between neurons. Such interneuronal communication may occur via dendrodendritic and axoaxonic gap junctions. Gap junctions also allow neighboring neurons to synchronize their signals through somatosomatic (cell body to cell body) connections, and they allow glial cells, especially astrocytes, to pass nutrient chemicals to neurons and to receive waste products from them.

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A neurotransmitter can influence a neuron’s functioning through a remarkable variety of mechanisms. In its direct actions in influencing a neuron’s electrical activity, however, a neurotransmitter acting through its receptors has only one of two effects. It influences transmembrane ion flow either to increase or to decrease the likelihood that the cell with which it comes in contact will produce an action potential. Thus, despite the wide variety of synapses, they all convey messages of only these two types, excitatory or inhibitory. To be precise, neurotransmitters themselves do not determine excitation or inhibition. The receptor makes the call.

Excitatory and inhibitory synapses differ in their appearance and are generally located on different parts of the neuron. As shown in Figure 5-7, excitatory synapses are typically on the shafts or spines of dendrites, whereas inhibitory synapses are typically on the cell body. Excitatory synapses have round synaptic vesicles; the vesicles in inhibitory synapses are flattened. The material on the presynaptic and postsynaptic membranes is denser in an excitatory synapse than it is in an inhibitory synapse, and the excitatory synaptic cleft is wider. Finally, the active zone on an excitatory synapse is larger than that on an inhibitory synapse.

The differing locations of excitatory and inhibitory synapses divide a neuron into two zones: an excitatory dendritic tree and an inhibitory cell body. Think of excitatory and inhibitory messages as interacting from these two different perspectives. Viewed from an inhibitory perspective, you can picture excitation coming in over the dendrites and spreading past the axon hillock to trigger an action potential at the initial segment. If the message is to be stopped, it is best stopped by inhibiting the cell body close to the initial segment. In this model of excitatory–inhibitory interaction, inhibition blocks excitation by a “cut ’em off at the pass” strategy.

Another way to conceptualize excitatory–inhibitory interaction is to picture excitation overcoming inhibition. In fact, excitatory synaptic inputs that are farther away from the soma are larger, to counteract the loss of signal that occurs over distance (Magee & Cook, 2000). If the cell body is typically in an inhibited state, the only way to generate an action potential is to reduce cell body inhibition. In this “open the gates” strategy, the excitatory message is like a racehorse ready to run down the track, but first the inhibitory starting gate must be removed.

Considering all the biochemical steps required for getting a message across a synapse and the variety of synapses, you might well wonder why—and how—such a complex communication system ever evolved. How did chemical transmitters originate?

To make the origin of chemical secretions for neuronal communication easier to imagine, think about the feeding behaviors of simple single-celled creatures. The earliest unicellular creatures secreted juices onto bacteria to immobilize and prepare them for ingestion. These digestive juices were probably expelled from the cell body by exocytosis: a vacuole or vesicle attaches itself to the cell membrane then opens into the extracellular fluid to discharge its contents. The prey thus immobilized is captured through the reverse process of endocytosis.

The exocytosis mechanism for digestion in a single-celled organism parallels its use to release a neurotransmitter for communication in more complex creatures. Quite possibly, evolution long ago adapted these primordial digestive processes into processes of neural communication in more complex organisms.

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A Chemical Message

Before you continue, check your understanding.

Question 1

Question 2

Question 3

Question 4

Question 5

Answers appear in the Self Test section of the book.