CHAPTER 5 SIGNALLING IN NEURONS

5.1. SYNAPTIC TRANSMISSION One of the main functions of neurons is to communicate with other neurons. An individual neuron may receive information from many different sources. Its job is to evaluate this information and "make a decision" as to whether to send out information to all of its target neurons, or whether to remain silent. It is hard to know where to begin describing the process of signalling in neural circuits, because signalling in any individual neuron depends on its getting input from other neurons that have been activated by the same processes that we will consider in our model neuron. The process of neural signalling is, in a sense, a cyclic process, so we can begin to describe it anywhere in the cycle and eventually come around to the starting point again. One logical point at which to start is the process of synaptic transmission, the transfer of information from one neuron (the presynaptic neuron) to another (the postsynaptic neuron) by release of a chemical substance, or neurotransmitter, from the axon terminal(s) of the presynaptic neuron. The neurotransmitter affects the state of the postsynaptic neuron, making it more or less likely to transmit information to its targets. Be aware that the terms presynaptic and postsynaptic are relative. A neuron that is presynaptic to its target neuron(s) will also be postsynaptic to one or more neurons that provide its input.

Figure 5-1. Pre- and postsynaptic neurons in a chain. Neuron A is presynaptic to neuron B. Neuron B is postsynaptic to neuron A, but presynaptic to neuron C.

5.1.1. The basic events in synaptic transmission. The process of synaptic transmission involves the following steps: Neurotransmitter molecules are synthesized in the cell body and transported down the axon to the synaptic ending (or terminal), where they are stored in small packets called vesicles. When the neuron is in a state that causes it to be "active", neurotransmitter is released from the vesicles into the synaptic cleft, or space between the axon terminal of one cell and the dendrite or cell body of another cell.

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Figure 5-2. The cell body contains the genetic information (DNA in the nucleus) and the synthetic apparatus (endoplasmic reticulum, Golgi apparatus) to make neurotransmitter molecules from their building blocks (e.g., amino acids) and package them in small membrane-covered spheres called vesicles. The vesicles are then transported down the axon to the synaptic terminals where they are accumulated in preparation for release. In this illustration, the synaptic terminals contact a muscle. They could also contact other neurons.

Figure 5-3. When a signal (action potential) is transmitted down the axon to the synaptic terminal, this causes vesicles to bind to the presynaptic membrane, where they rupture and release their contents into the synaptic cleft. The neurotransmitter molecules then bind to specialized receptor sites on the postsynaptic membrane, activating ligand-gated ion channels.

Neurotransmitter molecules bind to specialized receptor molecules on the postsynaptic cell membrane. Each type of receptor molecule has a high affinity for binding to a specific type of neurotransmitter molecule. The cell membrane of the postsynaptic neuron may have receptors for more than one kind of neurotransmitter. Receptor molecules may be associated with different types of ion channels on the cell membrane. An ion channel is a specialized pore that lets a specific type of ion pass through the

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cell membrane. Binding of the neurotransmitter molecule to the receptor causes the associated ion channel to open, letting ions pass through. 5.1.2. Neurotransmitters and graded potentials. There are many different molecules that can act as neurotransmitters. When small amounts of neurotransmitter are released, the resulting effect on the postsynaptic cell's membrane potential varies in proportion to the amount of neurotransmitter released, that is, the effect is graded. EPSPs. Some neurotransmitters are excitatory and cause depolarization, that is, they cause the inside of the cell to become more positive with respect to the outside. The resulting change in membrane potential is called an excitatory postsynaptic potential, or EPSP. Some of the most common excitatory neurotransmitters in the mammalian nervous system are glutamate and acetylcholine.

Figure 5-4. Graded potentials are best seen in intracellular recordings (recordings from the inside of a neuron). The vertical axis of the graph shows the membrane potential recorded from a neuron when it receives excitatory synaptic input. The neuron's resting potential is -70 mV. The line just below the shaded area represents its threshold for producing an action potential. The horizontal axis is time in milliseconds (ms = thousandths of a second). The size of the EPSP depends on how much excitatory input the neuron receives.

IPSPs. Some neurotransmitters are inhibitory and cause hyperpolarization, that is, they open a set of ion channels that allow negatively charged ions to enter the cell, causing the inside of the cell to become more negative with respect to the outside. The resulting change in membrane potential is called an inhibitory postsynaptic potential, or IPSP. Some of the most common inhibitory neurotransmitters in the mammalian nervous system are gamma-animo butyric acid (GABA) and glycine.

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Figure 5-5. When a neuron receives inhibitory synaptic input, a specific set of ligand-gated ion channels are activated, causing the membrane potential to become more negative, and thus farther away from threshold. Intracellular recording reveals the resulting change in membrane potential, or IPSP.

When a neuron receives input from one or more other other neurons, the resulting EPSP or IPSP is proportional to the size of the input The number of terminals releasing neurotransmitter, the total amount of neurotransmitter released, and the time course of neuroransmitter release all play a role in shaping the postsynaptic potential. If a cell receives an EPSP from one source and an IPSP from another source, they can partially or totally cancel one another, so intracellular recordings reflect the net effect of all presynaptic activity on the cell being studied. The graded potential (EPSP or IPSP) is not transmitted from one cell to another. Threshold. If an EPSP is large enough to cause the cell to depolarize to a certain value known as threshold, a different kind of electrical activity takes place. This activity is called an action potential. The action potential is transmitted down the cell's axon and causes neurotransmitter to be released onto the cell's target (postsynaptic) neuron(s). 5.2. THE ACTION POTENTIAL When one neuron receives input (i.e., neurotransmitter) from another neuron, its membrane potential changes. If it changes enough in the positive direction (i.e., depolarizes to threshold), a rapidly occurring process called an action potential is initiated. 5.2.1. The time-course of the action potential. The neuron's threshold is the membrane potential at which the action potential starts to occur. Once initiated, the action potential proceeds through several distinct stages:

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First, voltage-gated sodium (Na+) channels pop open, allowing Na+ to rush from the extracellular space into the cell, causing the interior of the cell to become even less negative with respect to the outside. At some point, the membrane potential actually becomes positive instead of negative. When the membrane potential becomes positive enough, the voltage-gated Na+ channels are inactivated and Na+ no longer enters the cell. At this point, voltage-gated K+ channels pop open, K+ rushes out of the cell, and the membrane potential becomes negative again (repolarizes). The rapid efflux of K+ from the cell causes a slight undershoot (hyperpolarization). Equilibrium is slowly restored through the action of the Na+/K+ pump.

Figure 5-6. If the neuron receives sufficient excitatory input, the resulting EPSP will be large enough to reach threshold (bottom border of shaded area). When that happens, voltage-gated ion channels open, allowing positively charged sodium ions to enter the inside of the cell. Intracellular recordings show this as a very large, very rapid change in membrane potential, the action potential. During the action potential, the inside of the cell becomes positive relative to the outside, and the influx of sodium is stopped. The cell then repolarizes. Usually there is a period of hyperpolarization at the end of the action potential.

5.2.2. Properties of the action potential. The action potential is commonly referred to as being "all-or-none". This means that, unlike an EPSP or IPSP, the action potential produced by a given neuron is always the same size regardless of how much neurotransmitter is present. Once initiated, the action potential is conducted along the axon to cause neurotransmitter to be released at a synapse on another cell. The action potential allows one neuron to communicate with others.

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5.2.3. Refractory period. Following an action potential, there is a certain time period during which it is difficult or impossible for the cell to generate another action potential. This means that neurons cannot fire an action potential more often than about once every millisecond. The absolute refractory period is the period during which another action potential cannot be generated under any circumstances. The relative refractory period is the period during which extra depolarizing current (an extra large EPSP) is needed to generate an action potential. 5.2.3. Response latency. Because synaptic transmission takes time, there is always a lag between the time a stimulus is present in the environment and the time a neuron responds. This lag time is called the response latency. This means that everything you perceive is actually something that happened a short while ago. The more synapses there are involved in processing a stimulus, the longer the response latency.

Figure 5-7. The process of synaptic transmission takes some time, so that there is a slight delay (about 1 millisecond) between the time the action potential reaches the presynaptic terminal and the time the postsynaptic neuron sends out an action potential (assuming it does). This delay is the response latency of the neuron

5.3. Interaction between inhibitory and excitatory synaptic inputs.

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Any neuron may receive both inhibitory and excitatory inputs. The output of the neuron depends on the relative strength and timing of these inputs, and can be thought of in a simplistic way as the algebraic sum of the two types of input at each point in time (the EPSP minus the IPSP). This means that EPSPs and IPSPs can sum over space and over time.

Figure 5-8. When EPSPs due to action potentials in input axons from different sources (A+B+C+D) all arrive at the postsynaptic cell at the same time, the effects are additive, and spatial summation results. This means that the EPSP produced by multiple inputs (solid line in "output" graph on right) is larger than any of the individual EPSPS would be if they occurred alone (dotted line in "output" graph on right).

Figure 5-9. When EPSPs due to non-simultaneous action potentials in one input axon or multiple input axons all arrive within a certain time range, the effects are additive, resulting in temporal summation. The longer the postsynaptic potential lasts, the more likely it is that temporal summation will occur. In the example on the left, each EPSP lasts a very short time (1 millisecond), so the EPSPs generated by action potentials spaced 2 milliseconds apart do not add. In the example on the right, each EPSP lasts 10 milliseconds (dotted line), so action potentials spaced 2 milliseconds apart do produce temporal summation. The duration of the EPSP (the time constant, t) is determined by the types of ion channels present on the postsyanptic cell.

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Thought question: The properties of neural synapses allow them to perform a wide variety of computational tasks. What are some of the computations that can be performed by groups of neurons with different patterns of excitatory and inhibitory connections and different sets of ion channels? _____________________________________________________________________________

_____________________________________________________________________________ Thought question: All neurons have absolute and relative refractory periods. What is the advantage of a refractory period in terms of neural processing and computation? _____________________________________________________________________________

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