Synaptic Transmission

Stephen D. Meriney, Erika Fanselow

• Publisher: Academic Press
• Year: 2019
• ISBN:
  9780128153215
• Topic: Biological Sciences
• Subtopic: Neuroscience
• Index: Biological Sciences

Synaptic Transmission is a comprehensive guide to the topic of neurotransmission that provides an in-depth discussion on many aspects of synapse structure and function—a fundamental part of the neuroscience discipline. Chapters include boxes that describe renowned/award-winning researchers and their contributions to the field of synaptic transmission, diseases relevant to the material presented, details of experimental approaches used to study synaptic transmission, and interesting asides that expand on topics covered. This book will inspire students to appreciate how the basic cellular and molecular biology of the synapse can lead to a better understanding of nervous system function and neurological disorders.

• Provides a comprehensive reference on synaptic structure, physiology, function and neurotransmission
• Discusses many landmark experiments in the field of synaptic transmission to emphasize core principles
• Includes references to primary scientific literature, relevant review articles and books, many of which could be assigned as discussion material for courses focused on this topic

Chapter 1

Introduction

Abstract

The nervous system is highly complex and is under active study. Progress in understanding the electrical and chemical basis for synaptic function depends on formulating and testing experimental hypotheses, many of which are tested in animal model systems. Information from these studies refines our ability to understand how synapses function in higher organisms and we can use this information to inform treatment of neurological disorders.

Keywords

Hypothesis; animal model system

The nervous system is essentially an information processing system that allows living organisms to control bodily functions, react to the environment, move, think, and display of emotions. At a basic level, all of these functions are governed by electrical activity within neurons and chemical communication between cells, which is referred to as synaptic transmission. Therefore, the phenomenon of synaptic transmission between cells represents a basic building block for understanding everything the nervous system does.

Take, for example, your reaction to someone throwing a ball toward you. You need to have cells that sense the ball flying toward you, cells to relay that information to other parts of the nervous system, and still other cells that help you decide what to do and then move muscles in your body accordingly. Furthermore, all of these cells respond (hopefully accurately!) within a fraction of a second to let you catch the ball. The mechanisms that underlie these processes include a combination of events that occur within neurons (basic cellular neurophysiology) and between neurons (synaptic transmission). In the chapters that follow, we will discuss many processes that govern how most cells in the nervous system communicate.

Hypothesis Development

Synaptic transmission is largely a hypothesis-driven field. This means that much of what we understand about how neurons communicate with one another is simply a proposed explanation based on limited experimental information for a given observation. This is referred to as a hypothesis. Initial hypotheses, in turn, form the basis for planning additional experiments that are designed to support, refine, or refute those and subsequent hypotheses and to provide further details about them. Because the study of synaptic transmission involves this process of repeatedly developing and refining hypotheses, it is still a constantly evolving field.

Therefore, to most convincingly present the material in this text, it is critical not only to outline the major hypotheses, but also to discuss the experimental support for those ideas. Because of this, the study of synaptic transmission is not simply pure memorization of facts, but rather of thinking critically about ideas. Toward this end, we have chosen particular hypotheses we believe drive home the fundamental principles of synaptic transmission, and we will take the student through the various experimental findings that came together to support them.

The Use of Animal Model Systems to Study Synapses

The study of synaptic transmission is focused on understanding the molecular and physiological bases of how neurons communicate with one another in the nervous system or on other cells affected by the nervous system. One of the main applications of this information is to understand and treat human neurological disorders. However, since detailed study of the human nervous system is not usually possible due to ethical, moral, and/or technical limitations, experiments that form the basis for our hypotheses are often performed using model systems. Model systems typically utilize simpler biological tissue and functions that allow us to learn the basic principles that underlie the function of the synapse. Such model systems can employ a specific type of cell and/or animal that is easier to study than mammalian brain synapses themselves. This use of animal model systems is based on the ethical use of these tissues as governed by national and local oversight agencies (https://www.ncbi.nlm.nih.gov/books/NBK24650/). With the accumulation of significant data from animal model systems, occasionally scientists have been able to use computational models to further explore hypotheses about synaptic function. These computational models are most productively employed when they can be used in conjunction with animal experimental data, but to date they do not replace basic animal research.

The use of nonmammalian animal model systems is particularly essential for the study of synapses because neuronal structures in mammals are typically very small and they are especially difficult to study in the mammalian central nervous system (see Fig. 1.1A). For example, a pyramidal cell in the hippocampus receives thousands of synapses, each contained within a small subcompartment of the neuron. When an experimenter is studying the details of the function of one of these mammalian hippocampal synapses, the task is difficult, in part due to the fact that so many other synapses onto that same pyramidal neuron are active at the same time. This might be akin to trying to understand a conversation with a person at a crowded party where everyone is talking at the same time. Some animal models provide the opportunity to clarify the details of synaptic function within one particular synapse in isolation.

Figure 1.1 Small central nervous system synapses as compared to larger model synapses.
(A) Thousands of synapses onto a cultured hippocampal neuron stained for a postsynaptic glutamate receptor subunit (green), a presynaptic vesicular glutamate transporter (red), and a marker for the postsynaptic hippocampal neuron cytoskeleton (blue). Each of the small red and yellow dots around the blue cell represents single synapses. (B) The large calyx of Held synapse from the auditory brainstem of the rat is so large that it is amenable to direct electrical recording from the nerve terminal. The presynaptic nerve terminal and axon are in yellow and the postsynaptic cell in blue. (C) A single neuromuscular junction of the mouse is very large and there is only one presynaptic nerve terminal onto each postsynaptic cell, making it easier to visualize transmitter release sites and simplifying the interpretation of synaptic transmission data. Scale bar in all images = 5 μm. Source: (A) Adapted from Journal of Neuroscience Cover art related to Ferreira, J.S., Schmidt, J., Rio, P., Águas, R., Rooyakkers, A., Li, K.W., et al. (2015). GluN2B-containing NMDA receptors regulate AMPA receptor traffic through anchoring of the synaptic proteasome. J. Neurosci., 35 (22), 8462–8479 (Ferreira et al., 2015); (B) Adapted from Borst, J.G., Helmchen, F., Sakmann, B., 1995. Pre- and postsynaptic whole-cell recordings in the medial nucleus of the trapezoid body of the rat. J. Physiol. 489 (Pt 3), 825–840 (Borst et al., 1995); (C) Ojala and Meriney, unpublished image.

Specific animal model systems are chosen for the experimental advantages they offer. These include larger or simpler synaptic structures and circuits, and/or synapses that are easier to remove and maintain outside the body during experimental study (see Fig. 1.1). That said, in some cases, the model systems used may be from higher-order animals when a synapse being studied has specializations that are not present in lower-order animals. In all cases, the rationale for the study of animal model systems is that basic principles learned in a model system can be applied to our understanding of function in more complex systems or higher-order animal species. The goal in designing these studies is to perform a critical experiment or test a hypothesis in a model system using a detailed approach that would not be possible in higher-order animals.

It is important to keep in mind that experiments in model systems often have limitations that should be taken into account when interpreting data. For example, studying the function of an ion channel when expressed in isolation in a frog egg or cultured kidney cell eliminates other modulatory proteins that might exist in the native environment of the neuron of interest. Such limitations are generally dictated by known differences between the model system and synapses in higher-order animals. However, when experiments using animal model systems are properly designed, the results will apply broadly to our understanding of synapses in higher organisms, including humans. Detailed experiments in simple model systems can sometimes be followed up with limited evaluations of the hypothesis in higher-order animals to confirm the validity of experimental findings in these species. In the following chapters, we will discuss many experiments for which this is the case.

References

1. Borst JG, Helmchen F, Sakmann B. Pre- and postsynaptic whole-cell recordings in the medial nucleus of the trapezoid body of the rat. J Physiol. 1995;489(Pt 3):825–840.

2. Ferreira JS, Schmidt J, Rio P, et al. GluN2B-containing NMDA receptors regulate AMPA receptor traffic through anchoring of the synaptic proteasome. J Neurosci. 2015;35(22):8462–8479.

Part I

Synaptic Biophysics and Nerve Terminal Structure

Outline

• Chapter 2 The Formation and Structure of Synapses
• Chapter 3 Basics of Cellular Neurophysiology
• Chapter 4 Ion Channels and Action Potential Generation
• Chapter 5 Electrical Synapses

Chapter 2

The Formation and Structure of Synapses

Abstract

The ability of neurons to send signals to one another is crucial for the function of the nervous system, but early scientists had no way of knowing how communication from one neuron to another occurred. We now take for granted that synapses exist between neurons, but before this could be verified using the advanced experimental techniques available relatively recently, there was debate among early neuroscientists about whether this was true. Some scientists proposed that neurons were contiguous with one another, much like capillaries in the body, while others concluded that neurons were in fact separate cells. This latter concept was called the Neuron Doctrine, which we now know to be correct. The junctions between neurons were given the name “synapse,” and the study of synapses has revealed ultrastructural details of synaptic structure as well as an understanding of how the nervous system assembles synapses during nervous system development.

Keywords

Reticular Theory; Neuron Doctrine; synapse structure; synapse formation; synapse development

How Do Neurons Send Signals to One Another?

We will start with an historical perspective on the study of synapses. In the 19th century, scientists developed methods for labeling cells of the nervous system with dyes. Initially, researchers used dyes that labeled only the neuron cell body and sometimes a few cellular compartments near the edge of the cell body. This microscopic cell labeling showed that neurons were not like other cells in the body, which often appeared as isolated round spheres. Instead, it became clear that neurons had long extensions leaving the cell body, which we now know to be axons, as well as overlapping highly branched structures, which we now know to be dendrites. These early observations gave the impression that neurons were directly connected to, and indeed, contiguous with, one another. However, these early images of neurons did not allow scientists to view the very ends of axons or dendrites, or the actual connections between neurons. As such, connections ...