LESSON 3.2 WORKBOOK How do our neurons communicate with each other? This lesson introduces you to how one neuron communicates with another neuron during the process of synaptic transmission. In this lesson you will learn how the electrical signal of the action potential is converted into a chemical signal at the nerve terminal, and how this chemical signal crosses the small gap, the synapse, between the presynaptic and the postsynaptic neuron. Getting pain to the brain Pain pathways deliver information about painful stimuli (nociceptive information) using an ascending pathway that travels from the nociceptive receptors in the periphery to the brain. The pathway has four important neurons, each of which plays a different role in transmitting and interpreting the painful signal (Figure 2): The first, or primary, neuron is at the very beginning of the pathway. The end of its dendrites in the periphery is where the nociceptive stimulus is first encountered. Its presynaptic terminal is in the spinal cord and connects with.. The dendrites of the second neuron, which is located in the spinal cord. This neuron gathers nociceptive information from several primary neurons into distinct pathways that ascend in the white matter of the spinal cord. Their presynaptic terminals are in the thalamus and connect with The third neuron, which is located in the thalamus. The thalamus is like a post office that gathers information and sends it to the right place in the cortex. So their presynaptic terminals are in the cortex where they connect with Neurons in region of the cortex that deals with receiving sensory information about pain (somatosensory cortex). Within the cortex these neurons also communicate with cortical areas having other information about the environment and emotion, so that the body can initiate a response. Lesson 3.2 Now that we know about the four neurons involved in getting pain information to the brain, let s focus on 77 how the neurons communicate with each other at the synapses between them. What are the four neurons involved in getting pain to the brain? Where are they and what role do they play in the pathway?
DEFINITIONS OF TERMS Neurotransmitters chemicals that are released by the axon terminal and convey the message across the synapse to another cell. Postsynaptic potentials small changes in voltage (membrane potential) due to the binding of neurotransmitter. Receptors proteins that contain binding sites for particular neurotransmitters. For a complete list of defined terms, see the Glossary. LESSON READING An introduction to synaptic transmission Synaptic transmission is the major way that neurons communicate with each other across the small gap between the presynaptic site and postsynaptic site called the synaptic cleft. When we left the presynaptic terminal, an electrical signal the action potential had traveled down the axon. However the action potential, being electric, can t jump the synaptic cleft between the pre- and postsynaptic sites. To transmit the message to the postsynaptic site the neuron must convert the electrical signal to a chemical one. This chemical signal is carried by neurotransmitters chemicals that are released when the axon terminal is stimulated by the action potential. Motor neuron Sensory neuron Interneuron Projec'on neuron Figure 2: The synapses in the pain pathway. The synapses in the pain pathway allow for modulation of pain stimuli. The first synapse is in the periphery, where nociceptors are initially activated. The second synapse is in the spinal cord. The third synapse is in the thalamus (not shown here) and the fourth synapse is in the cortex. The neurotransmitters diffuse across the synaptic cleft to the postsynaptic site where they bind to specific receptors that recognize them on the postsynaptic membrane. Once the neurotransmitter has bound to the receptor it can produce a postsynaptic potential a brief depolarization or hyperpolarization in the postsynaptic membrane that happens because the neurotransmitter receptors themselves are associated with ion channels. If enough postsynaptic potentials occur, the membrane may be pushed toward or away from threshold, depending on whether the membrane has depolarized or hyperpolarized, increasing or decreasing the likelihood of the postsynaptic neuron firing an action potential and sending the signal down its axon to another synapse. Since there are obviously several steps involved in synaptic transmission, let s investigate each one in more detail. We ll start our more detailed discussion of synaptic transmission by taking a closer look at the synapse. How is synaptic transmission different from the action potential? Compare where the two signals occur and how the signal is sent. Lesson 3.2 78
DEFINITIONS OF TERMS Synaptic vesicles small spherical membranes that store neurotransmitters and release them into the synaptic cleft For a complete list of defined terms, see the Glossary. LESSON READING The Synapse The word synapse was coined in 1897 by the British physiologist Sir Charles Sherrington (Figure 3) from the Greek word synapo, which means to clasp. Using only a light microscope, Sherrington could not see the actual point of communication between neurons, but his experiments had shown that transmission can only occur in one direction (from what we now call the presynaptic cell to the postsynaptic cell). Sherrington even correctly inferred that the sending (presynaptic) and receiving (postsynaptic) cells do not actually touch each other. Presynap)c membrane Postsynap)c membrane Microtubule Mitochondrion The presynaptic terminal Presynap)c cell Postsynap)c cell Figure 4: Structure of a typical synapse. The presynaptic membrane faces the postsynaptic membrane. Notice that the presynaptic cell contains both large and small synaptic vesicles, mitochondria and microtubules. Notice that the postsynaptic membrane contains receptors sites that will bind neurotransmitter. Axon Figure 3: Sir Charles Sherrington (1857 1952). For his work, he was awarded the Nobel Prize for Physiology or Medicine in 1932. Figure 4 illustrates a synapse. The presynaptic membrane, located at the end of the axon terminal, faces the postsynaptic membrane, located on the neuron receiving the information. These two membranes face each other across the synaptic cleft, a gap that varies in size from synapse to synapse but is usually around 20 nanometers (nm) wide. As you may have noticed in Figure 4, the axon terminal contains two prominent structures: mitochondria and synaptic vesicles. (We can also see the microtubules, which as you will remember are responsible for transporting the mitochondria and vesicles from the cell body where they are made to the terminal.) Because the terminal is often swollen to contain all this material it is often called the terminal button or more precisely bouton, which is simply button in French. Recall from Unit 2 that vesicles are small, hollow, beadlike structures that are transported down the axon from the cell body. In the synaptic terminal most of them are filled with neurotransmitters and become synaptic vesicles. Axon terminals can contain as few as a few hundred and as many as nearly a million Why do you think mitochondria are located in the presynaptic terminal? Lesson 3.2 synaptic vesicles. 79
LESSON READING The postsynaptic terminal The picture in Figure 5 was taken with a very high resolution electron microscope, and shows that the postsynaptic membrane appears somewhat thicker and more dense than the membrane elsewhere. This increased density occurs because the postsynpatic membrane is loaded with neurotransmitter receptors specialized proteins that detect the presence of neurotransmitter in the synaptic cleft because the neurotransmitters bind to them very specifically. What are neurotransmitters? Neurotransmitters are the chemicals neurons release in order to communicate with other cells. Scientists first thought that only a few chemicals were involved in neurotransmission, but we have now identified over 100 different neurotransmitters. Fortunately, most of them conveniently fall into a small number of chemical classes. See Box 3.1 for descriptions of your body s primary neurotransmitters. BOX 3.1: Your Neurotransmitters Figure 5: Electron micrography of an synapse. This photography shows a cross section of a synapse. The axon terminal is filled with synaptic vesicles (upper left corner). The postsynaptic membrane on the dendritic spine appears thicker and denser than the other membranes; this is due to the presence of receptors. There are more than a hundred different neurotransmitters, with more being discovered all the time. Scientists are finding that many hormones can also play the role of transmitter as well. Here are some the neurotransmitters your brain uses every day: Acetylcholine (ACh) gets us going. It excites cells, activates muscles, and is involved in wakefulness, attentiveness, anger, aggression, and sexuality. Alzheimer s disease is associated with a shortage of acetylcholine. Glutamate is a major neurotransmitter that excites other neurons. It is dispersed widely throughout the brain. It s involved in learning and memory. GABA (gamma-aminobutyric acid) is your brain s main inhibitory neurotransmitter. It slows everything down and helps keep your systems in balance. It helps regulate anxiety. Epinephrine, also known as adrenaline, keeps you alert and your blood pressure balanced, and it jumps in when you need energy. It s produced and released by the adrenal glands in times of stress. Too much can increase anxiety or tension. Norepinephrine (noradrenaline) is a precursor and has similar actions. Dopamine (DA) is vital for voluntary movement, attentiveness, motivation and pleasure. It s a key player in addiction, so we ll discuss it again in Unit 5. What neurotransmitters have you heard of before and in what context? Lesson 3.2 Serotonin helps regulate body temperature, memory, emotion, sleep, appetite, and mood. Many antidepressants work by regulating serotonin. 80
DEFINITIONS OF TERMS Exocytosis process by which the contents of membrane bound vesicle are released to the exterior through fusion of the vesicle membrane with the cell membrane. For a complete list of defined terms, see the Glossary. LESSON READING Release of neurotransmitter When action potentials are conducted down the axon and enter the presynaptic terminal, something happens inside the terminals a number of small synaptic vesicles spill their contents into the synaptic cleft (Figure 6). 1. 2. 3. 6. Figure 6: Steps involved in synaptic transmission. See text for descriptions, then write your own summary. 4. 5. How does an action potential cause synaptic vesicles to release neurotransmitter into the synaptic cleft? The process begins when an action potential invades the presynaptic terminal (Figure 6: Step 1). Then, some of the synaptic vesicles closest to presynaptic membrane become docked at a region in the presynaptic terminal called the active zone. Docking happens when clusters of proteins on the outside of the synaptic vesicle attach to other proteins located on the inside of the active zone. Once they are docked, synaptic vesicles are ready to release their neurotransmitter into the synaptic cleft. Synaptic vesicles only release their neurotransmitter when the action potential tells them to. How does this happen? We need to introduce another player located at the presynaptic terminals the voltagegated calcium channel. Voltage-gated calcium channels are similar to voltage-gated sodium channels in that they only open when the membrane depolarizes. They are different from voltage-gated sodium channels because they are permeable to calcium ions (Ca 2+ ), not Na + ions. Like Na + ions, calcium ions (Ca 2+ ) are located in highest concentration in the extracellular fluid, so when an action potential arrives at the presynaptic terminal and depolarizes the membrane, the calcium channels open and Ca 2+ floods into the presynaptic terminal, propelled by the forces of diffusion and electrostatic pressure as we talked about in Lesson 2.2 (Figure 6: Step 2). The entry of Ca 2+ into the presynaptic terminal is an essential step in synaptic transmission because it gives the synaptic vesicles the signal to release their neurotransmitter into the synaptic cleft. The Ca 2+ ions bind with the cluster of proteins that docked the membrane of the synaptic vesicles with the active zone. The binding of Ca 2+ changes the shape of these proteins, making them move apart. As they move apart a hole or pore appears in both the synaptic vesicle and the active zone it is attached to. Both membranes then form a fusion pore so the synaptic vesicles can release their contents into the synaptic cleft. The arrival of an action potential triggers the release of neurotransmitters. How does it trigger this release? The entry calcium ions into the presynaptic terminal is another important step in the release of neurotransmitter. What happens after calcium levels rise? With synaptic vesicles fusing to the presynaptic membrane, how does the presynaptic membrane not just continually increase in size? Lesson 3.2 Another name for this process of fusion and release is exocytosis (Figure 6: Step 3). 81
DEFINITIONS OF TERMS Endocytosis process by which matter is taken in by a living cell by invagination of its membrane to form a vesicle. Postsynaptic potentials small changes in voltage (membrane potential) due to the binding of neurotransmitter. For a complete list of defined terms, see the Glossary. LESSON READING What happens to the membrane of the synaptic vesicles after they have broken open and released the neurotransmitter they contain? If the open vesicles have not completely collapsed onto the presynaptic membrane they can simply pinch off again and drift away to be filled once more with neurotransmitter. This has been called kiss and run. Other times the fusion pore becomes so large that the vesicles seem to flatten down and merge entirely with the presynaptic membrane. In these cases the little buds of the presynaptic membrane pinch off back into the terminal, effectively creating new synaptic vesicles. Another name for this process of pinching off and recovery is endocytosis. Activation of receptors How does the release of neurotransmitters from the presynaptic terminal into the synaptic cleft produce an effect in the postsynaptic cell? The answer to this question begins with the binding of neurotransmitters to their receptors on the postsynaptic cell membrane (Figure 6: Step 4). Once this binding occurs, the postsynaptic receptors too change their shapes, and in the process open ion channels located in the postsynaptic membrane. These ion channels, which are called receptor-gated ion channels, because they are activated by receptors, not by voltage, permit specific ions to pass into or out of the postsynaptic cell (Figure 6: Step 5). Thus, the neurotransmitter in the synaptic cleft, by binding to receptors, allows particular ions to pass through the postsynaptic cell s membrane, changing the membrane potential at the postsynaptic site and creating postsynaptic potentials. Termination of synaptic transmission Postsynaptic potentials are therefore brief changes in the postsynaptic membrane potential caused by the activation of postsynaptic receptors by neurotransmitters. They are kept brief because the neurotransmitter is rapidly removed from the synaptic cleft, and once it is removed it can no longer activate its receptors. Neurotransmitters can be removed by two mechanisms: Reuptake Degradation by enzymes Almost all central nervous system neurotransmitters are removed by reuptake (Figure 6: Step 6). This simply involves taking the neurotransmitter back into the presynaptic terminal again, using a special energy-dependent pump called a transporter. This means that from the time that an action potential stimulates release of neurotransmitter into the synaptic cleft, until the presynaptic terminal takes it back up again, the postsynaptic receptors only have a brief exposure to the neurotransmitter. The process of reuptake ensures that postsynaptic potentials are also quite brief. The binding of neurotransmitters to receptors causes ion channels to open, thus changing the membrane potential in the postsynaptic neuron. Can you predict how this change in membrane potential might affect the postsynaptic neuron? What might result from this change in membrane potential? Certain drugs inhibit the reuptake of neurotransmitter from the synaptic cleft. What would happen if this reuptake was blocked? Lesson 3.2 82
LESSON READING Neurotransmitters can also be broken down in the synaptic cleft by enzymes. As far as we know only one neurotransmitter is dealt with in this way, but it is an important one. Acetylcholine (ACh) is the neurotransmitter used at our neuromuscular junctions, where neurons instruct our muscles to contract. It is critical that the postsynaptic potentials produced by ACh be short-lived because the quick breakdown of ACh is important for us to have tight control over the timing of muscle contraction. So at the neuromuscular junction the synaptic cleft is awash with the specific enzyme that can chew up ACh, and stop it binding to its receptor. Summary In conclusion remember that the communication between neurons requires several steps. First the presynaptic cell must fire an action potential. Once the action potential invades the presynaptic axon terminal, the presynaptic cell releases neurotransmitters into the synaptic cleft. These neurotransmitters then cross the synapse and bind to receptors on the postsynaptic cell. After binding to receptors, neurotransmitters cause postsynaptic potentials in the postsynaptic cell. What do you predict would be the effect of drugs or toxins that stop the breakdown of ACh in the neuromuscular junction? Lesson 3.2 83
STUDENT RESPONSES On the diagram below, label and describe the steps of synaptic transmission. The goal of synaptic transmission is to send a signal from one neuron to another. Does it matter which ions channels open and which ions flow into the postsynaptic cell? (Hint: Think about the effect positive and negative ions would have on the chances of the postsynaptic neuron reaching threshold.) Lesson 3.2 84