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Well Connected

John Horn

Synapses. W. Maxwell Cowan, Thomas C. Südhof and Charles F. Stevens, eds. xvi + 767 pp. The Johns Hopkins University Press, 2001. $69.95.

Understanding the brain remains one of the great challenges in science. How do simple biological mechanisms give rise to the complexities of perception, learning and behavior? Can cellular biology ever illuminate consciousness, conscience or cognition? The notion that an analysis of synapses may provide the key to such questions has become a central tenet of modern neuroscience. Synapses adds grist to this mill, which makes it an important book.

A distinguished group of authors who had participated in a workshop sponsored by the Howard Hughes Medical Institute in June of 1999 were invited to write the 15 review essays brought together here. All of the essays reflect upon subjects of intense, fast-moving research. In most cases, the authors have provided an engaging and readily accessible critical review with a lucid introduction, not just a catalogue of the primary literature.

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Synapses should appeal to a broad audience. It covers an astounding array of interesting topics, including the molecular control of secretion, synaptic structure, neuronal cell recognition and gene expression, the physiology and biophysics of synaptic transmission and plasticity, the relation between genes and behavior, mechanisms of synaptic development, novel neurotransmitters, and Monte Carlo simulations of subcellular dynamics during synaptic transmission. As is often the case with edited volumes, the book's length coupled with its diversity may deter all but the most avid readers. Fortunately, one can pick and choose among individual chapters, because they easily stand on their own.

Can readers without a background or active interest in neuroscience benefit from this book? I think the answer is a qualified yes. The qualification requires that we step back, define the synapse and then delineate the questions that motivate molecular and cellular approaches to synaptic function.

Synapses are specialized anatomical junctions that enable neurons to communicate with one another and with the world by way of sensory organs, muscles and glands. Neurons convey signals across synapses by secreting chemical messengers known as neurotransmitters. Once released, neurotransmitters induce synaptic potentials and biochemical events in target cells by binding to receptors in the plasma membrane. On short time scales of milliseconds to minutes, temporal interactions between synaptic potentials initiate the brief regenerative electrical impulses called action potentials. These so-called "spikes" are believed to be the universal token of neural information. It remains unclear whether information is coded by the rate at which individual neurons fire action potentials, by the precise timing of action potentials in large arrays of cells, or by combinations of both schemes. In all of these scenarios, synapses mediate the transfer and transformation of spike traffic from one cell to the next. On longer time scales, both electrical activity and receptor-mediated stimulation can activate numerous signal transduction pathways, thereby producing myriad effects on cellular behavior, including changes in gene expression. In this manner, synapses provide a critical linkage between the moment-to-moment genesis of behavior and long-term regulation of nervous function.

The authors of Synapses, along with many others in the field, seek to answer three basic questions in molecular terms: How do synapses regulate the firing of action potentials and gene expression? How are neural circuits constructed during development and modified by experience? and How do changes in the strength and character of synaptic connections give rise to perception, learning, memory and behavior? Any reader with an appreciation of these questions and a passing knowledge of biology will profit from this collection.

The book begins with a wonderful historical review by Max Cowan and Eric Kandel of the classical period from 1880 to 1980, during which synapses were first discovered, defined and analyzed. Although much of the information in this chapter can be found in other contemporary reviews, these old hands bring to bear their unique perspectives on the history of the field. By recounting some of the early struggles, they illustrate the enduring value of clear mechanistic hypotheses and adequate experimental methods. Younger readers should take heart on reading that contemporary quagmires (such as the mechanism of long-term potentiation) have multiple precedents in previous generations.

This chapter also reminds us how preparations of the neuromuscular junction and of autonomic ganglia made it possible to identify the first neurotransmitters (acetylcholine and norepinephrine). From this grew the classical paradigm for synaptic transmission, which still lies at the core of all modern work. Since the early 1980s, technical advances in physiology and molecular biology have spurred a large-scale migration to the analysis of synapses in the brain, where glutamate and g-aminobutyric acid (GABA) are the predominant transmitters. These threads, beautifully laid down by Cowan and Kandel, are followed through all the remaining chapters.

Several other chapters stand out because of their clarity and broad appeal. Wade Regehr and Charles Stevens summarize with elegant simplicity modern approaches to synaptic electrophysiology, quantal analysis and the dynamics of short-term plasticity (for example, facilitation and depression). Thomas Südhof presents a masterful review of synaptic adhesion molecules that should appeal to novices and experts alike. Rob Malenka and Steve Siegelbaum tackle the thorny issue of long-term potentiation and provide one of the most lucid explanations to date of the conflicting data that cloud this seminal problem.

Paul Grimwood, Stephen Martin and Richard Morris provide a somewhat discomfiting discussion of the problems of behavioral analysis, which should be considered by all who hope to test molecular hypotheses of behavior using transgenic animals. Edward Lein and Carla Shatz review the fascinating hypothesis that neurotrophins may serve to regulate the critical period for establishment of ocular dominance columns in primary visual cortex. And Solomon Snyder and Christopher Ferris explain how the discovery of gaseous signaling molecules (nitric oxide and carbon monoxide) serves to challenge the definition of neurotransmitters; they also discuss additional conceptual changes that may lie ahead.

My only real criticism, and this is debatable, is that Synapses is less well-integrated than one might have hoped. Thus it has too many separate chapters for me to even mention them all. Indeed, the challenge in this field lies not only in expanding our grasp but also in consolidating our understanding. It was presumably by design that the editors chose to emphasize molecular and cellular mechanisms at the expense of circuits, systems and behavior. One can do only so much in a single volume. Perhaps the editors should consider future volumes dedicated to these other levels of analysis, and to the most difficult problem—crossing between them.

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