Information Released on the Synapse

Information is transferred from one nerve cell to the next by regulated release of neurotransmitter. This normally occurs at specialized connections called synapses, where a complex molecular machinery is assembled to control sustained transmitter release. The discovery over 40 years ago that neurotransmitter is released in packets called quanta, together with the ultrastructural characterization of synapses, focused attention on synaptic vesicles as key organelles of neurotransmitter release. Synaptic vesicles are targeted to and cluster at special regions of the axon, where they undergo regulated fusion. Electrical signals arriving at the presynaptic terminal cause calcium influx, which in turn triggers a set of molecular events leading to the fusion of synaptic vesicles with the plasma membrane and the emptying of neurotransmitter into the synaptic cleft. In the last decade, significant advances have been made in understanding the molecular basis of transmitter release, and Neurotransmitter Release: Frontiers in Molecular Biology provides an up-to-date synthesis of facts and ideas on this subject.A major part of current research in synaptic transmission is focused on understanding the series of protein–protein and protein–lipid interactions underlying the life cycle of the synaptic vesicle. Synaptic vesicles probably need to be docked to the active zone before they can fuse with the membrane. How vesicles recognize the active zone and remain docked there (and not elsewhere in the presynaptic plasma membrane) remains largely a mystery. Although there is evidence for the role of rab proteins and SNARE proteins in the docking step, neither class appears currently to have all the attributes of a molecular device mediating selective target recognition. Once docked, vesicles are thought to undergo maturation reactions, referred to as priming, before they become fusion competent. Then, an increase in intraterminal calcium leads to fusion of the vesicle with the plasma membrane—this step probably involves the SNARE proteins, but the exact nature of the reaction leading to fusion is unclear at present. Once exocytosis occurs, vesicular components are retrieved for reuse by clathrin-mediated, and perhaps other forms of endocytosis. The recycling machinery at the synapse no doubt has much in common with other cellular endocytic pathways. The key components of the endocytic machinery are being uncovered, but the exact signals for and mechanisms of endocytosis remain hidden.A remarkable similarity of proteins involved in secretion in different cell types and across species has allowed the integration of data from different model systems and organisms. For example, homologs of many of the proteins that mediate secretion in yeast are involved in neurotransmitter release. Given the rapid growth of factual knowledge about membrane traffic in general, it is becoming increasingly difficult, though necessary, for a specialist to keep track of developments in such diverse fields as cell division in yeast and synapse formation in mouse. Therefore, Neurotransmitter Release provides a welcome compilation of the latest information on the molecular basis of synaptic vesicle traffic.The book is well organized. It starts with an overview of the cell biology of the synapse, which is followed by a chapter reviewing key physiological techniques used to measure synaptic function. Oddly enough, this chapter on techniques does not consider the classical electrophysiological method of measuring postsynaptic current to assay vesicle exocytosis (this method, however, is invoked extensively in a later chapter describing the use of the squid giant synapse as a model system). Chapter 3 presents a comprehensive account of proteins involved in membrane trafficking at synapses, touching upon the history of identification of synaptic proteins and their characterization. This chapter also provides information about the structure of proteins involved in vesicle fusion, and detailed discussion of current ideas of how membrane fusion might occur. Chapter 4 describes the role of membrane phospholipids, particularly phosphoinositides, in signaling as well as regulation of protein function at the synapse. The chapter on neurotransmitter transporters at synapses is a veritable encyclopedia, and with its nearly 400 references will surely serve as a valuable resource. Neurotoxins have greatly aided the understanding of the role of specific proteins in neurotransmission, and chapter 6 describes the mechanism of action and targets of many of these toxins. The four subsequent chapters focus on specific model systems—first the squid giant synapse, which has aided in detailed physiological and morphological studies of transmitter release. Three other systems where genetic manipulations have provided enormous insight into mechanisms of synaptic function—C. elegans, Drosophila, and mouse—are described next. The general style of these three chapters is to first describe the methods used to obtain mutant or transgenic animals, followed by a discussion of different genes and gene products identified from mutants. A final chapter on endocytosis and vesicle recycling informs us about the tremendous advances made in this area in the last few years.Despite the stylistic and linguistic differences inevitable in a multiple-author book, Neurotransmitter Release is eminently readable. The references to primary papers are extensive, and the overlapping content of different chapters serves to reinforce key ideas. Another satisfying aspect of the book is the integration of information from several model systems and organisms. For example, the key components of membrane fusion—the SNARE proteins and proteins interacting with them—are discussed in almost every chapter. Likewise, proteins involved in endocytosis—such as clathrin, dynamin, and amphiphysin—crop up in most chapters. In the preface, Hugo Bellen, the editor of the volume, says that “most chapters emphasize the thought process by which proteins are assigned specific functions rather than providing facts about function.” This is largely true, and a graduate student looking for experimental methods to answer a question can reasonably expect to find a starting point in the book.Genetic approaches are understandably emphasized in much of the book, and they will no doubt continue to contribute in the discovery of proteins essential for different steps of synaptic transmission. Less transparent in much of the book, however, is a mechanistic, physicochemical explanation of specific processes in vesicle trafficking. With a complete parts list that will become available to us soon as a result of the hard work of the last few decades, future effort will no doubt be aimed at understanding mechanisms in a physical sense.Given the broad interest in synaptic modification, a chapter devoted to the regulation of neurotransmitter release would have been welcome. Like many other biological signaling systems, synapses adapt. This feature requires the synapse to have an intricate set of regulatory elements. Synaptic adaptation probably contributes to ongoing computations performed by neural circuits, as well as to the storage of memories by these same circuits. Many of the steps in presynaptic vesicle trafficking appear to have the potential for regulation, and an exploration of this would be of general interest.In the history of synaptic transmission, one book stands out as a classic. This is Bernard Katz's Release of Neurotransmitter Substances, which conveyed key ideas of neurotransmission elegantly, without sacrificing depth of analysis. With the mass of data we have now, it is unclear if such a book can be written today. Generalizations and extraction of fundamental principles seem difficult given the tremendous complexity of even so-called simple systems; one needs to read just a few pages of Neurotransmitter Release to appreciate this. Still, many of the authors manage to summarize in key figures what is known about specific processes (exocytosis, for example). So, whether you are the type that strives for generalization or one that revels in the details, Neurotransmitter Release should prove stimulating.