In neurosciences one may say, '"All roads lead to Rome. " It seems as though wherever one starts, the course of investigation leads to the same major ques tions about nervous system function and dysfunction. In thinking about what to write in this preface, it occurred to me that it might be best to deal with that with which I am most familiar and to trace to some extent my own '"road to Rome. '' As I look over my work of the last 37 years, it becomes clear to me that it can be epitomized as a search for patterns. What usually began as a single minded devotion to in-depth analysis of one or a small number of variables always has led to questions of how the results might relate to the whole living unit, whether it is cell, tissue, or organism. For a number of years after my discovery in the vertebrate central nervous system of -y-aminobutyric acid (GABA) and the enzyme which forms it, L glutamate decarboxylase (GAD), and the identification of GABA as a major inhibitory neurotransmitter by others, I felt that my laboratory, largely bio chemical, was wandering in the wilderness of the complexities of the vertebrate CNS without definitively coming to terms with problems related to GABAergic transmitter functions and the roles of GABA neurons in information processing."

This volume is concerned with the enzymes of the nervous system. Cerebral enzymes form the basis of the functional brain. They are needed for the control of the energetics of the nervous system, whether it be their release or their direction; for the elaboration of transmitters and for their destruction; for the synthesis, transport, and breakdown of all metabolites of the nervous system. They are indispensable for the control of the multitude of factors that govern our thinking and our behavior. They make it possible for us to comprehend what is taking place around us and perhaps to understand what may be in store for us. Enzymes are the stuff of life, and no living cell can be without them. They are the results of many millions of years of evolution, from the time when biological membranes first came into being and were folded to produce the first cells within which the earliest enzymes were wrought. Countless changes have taken place within them, so that, now, only those enzymes exist that play specific roles in the functions of the living cells of today. Those in the nervous system possess a mUltiple role: in the creation, maintenance, and ultimate breakdown of the component cells and in enabling consciousness, perception, memory, and thought to become possible. But though life may go on forever, the enzymes that make life possible will undergo the many changes involved in the evolutionary process.

A major advance in the biological sciences in the past decade has been the biochemical identification of cell membrane receptors. The existence of re ceptor substances on the surface of cells that recognize and bind to extracellular molecules was proposed at the beginning of the century by the pharmacologist and immunologist Paul Ehrlich and the physiologist J. N. Langley. Since then, receptors have been found to play an important role in numerous physiological and pathological processes. Over the years many attempts have been made to physically isolate and chemically characterize receptors, but because of the receptors' extremely low concentration and membrane localization, these ef forts have met with limited success. Yet, despite the failure to characterize receptor substances, the concept of the presence of such molecules has had considerable heuristic value. Using pharmacological, physiological, and im munologic approaches, researchers have identified several specific receptors, e. g. , a-and ~-adrenergic, nicotinic and muscarinic cholinergic, and histami nergic. With the characterization of various types of receptors on cell mem branes, many drugs were developed that proved to be experimentally and ther apeutically useful. It was only in the early 1970s that methods for the specific measurement, chemical characterization, and physical isolation of cell membrane receptors were developed. These advances were made possible by the availability of ligands with high specific radioactivity that retained their biological activity and of experimental procedures that differentiated between specific and non specific binding of ligands.

That chemicals (although not always called by this name) affect the brain and its functions, such as behavior, has been known for thousands of years. It is therefore surprising that the concept that chemical mechanisms are at least partially responsible for the complex functions of the brain is so recent. Investigation of the closely interlinked biophysical and biochemical proper ties of the nervous system has achieved many notable successes in recent years and is the most exciting development in 20th-century science. Although all the morphology, the activity, and the alteration of the brain, whether bioelectric, biochemical, pathological, or structural, constitute an organic and indivisible whole, the ambition of the Handbook is to look at only a few aspects of this whole and to focus the discussions on the experi ments that the neurochemists have performed. Neurochemical study of the nervous system has, perhaps of necessity, gone through several phases: the first phase was more analytical and in volved study of the composition of the tissue; the second, more recent phase clarified many of the metabolic sequences that occur in this tissue. Clearly, both were essential, but they showed that additional approaches are neces sary. The present phase seems to be the study of control processes; present interest focuses on what determines, in a qualitative and quantitative fashion, the processes occurring in the nervous system. Perhaps the next phase will be the study of function, the study of the final stage of integration.

When the projected volumes of the Handbook are completed, most of our current knowledge of the biochemistry of nervous systems will have been touched upon. A number of the chapters will have dealt with the correlations of the biochemical findings with morphological and physio logical parameters as well. Considering the abysmal lack of such attempts, even in the recent past, this is a sign of great progress. If the reader's eventual goal is to derive the "laws" that relate various aspects of animal and human behavior to underlying physiological and biochemical function, these admirable volumes will help him to establish a firm biochemical base from which to operate. It is certain that the future approaches to the various problems of the information-processing functions of the nervous system will require an integrated understanding of the essence of all of the scientific disciplines which are grouped under the general name of neuro biology. The rich feast of information offered up in this Handbook will enable those in the non-chemical disciplines to pick and choose those areas of chemical information pertinent to their immediate interests. Similar types of compendia by physiologists, anatomists, cyberneticists, and psychologists have been helpful to chemists and continue to be so.

Life, either as we think of it in the abstract in its highest sense, or life, as we think of it in terms of a compact living organism, is obviously the result of complex interaction of all of the components of the organism. One could therefore question the advisability of separating out the nervous system for a special detailed study in our age of overspecialization. The main purpose of the present Handbook is not to fragment further our approach or under standing of living phenomena, but, on the contrary, to try to summarize and integrate as much of the available information and thinking on the nervous system as is possible in a limited space. It is difficult to think of an area of modern biology that is more exciting to study and that has greater impor tance for mankind, from any point of view, than the study of the brain and of the nervous system. The influence that understanding of brain function in biological terms can exert on our future is not generally understood in its full impact. Although our ignorance about even the most basic mechanisms in the nervous system is enormous, in recent years our knowledge has made most important advances, and as a consequence great masses of data have been accumulated.

After the completion of the first edition of this series, this editor thought that a new edition would not be warranted in less than IS, perhaps 20, years, but it seems that we live in a time in which rapid changes are the norm and findings in a field such as neurochemistry develop exponentially. The task of a future editor attempting to get a comprehensive neurochemical handbook for the year 2000 would be even less enviable, but by then information processing may be very different. The approach, the design, and the areas covered by each volume and each chapter are necessarily arbitrary, and it is likely that other editors or authors would have approached the coverage or the organization in a different manner. It is hoped, however, that readers will find the series helpful for beginning or for continuing work. There may be some overlap among the various chapters, but insisting on single coverage of an area would at times have restricted treatment to only one point of view and might have truncated and hurt the logical flow of some of the chapters.

The explosive accumulation of new knowledge in the biological sciences in the last decades has advanced our understanding of the basic mechanisms that underlie most biological phenomena. These advances, however, have not been uniform but have varied considerably among the different biological problems. In some cases, e.g., biochemical genetics, radical advances have been made which have changed our ideas and our approaches. In other cases, even with work which has yielded much detailed new knowledge, our under standing of basic mechanisms remains very inadequate. Among the lines of work that have not yet led to dramatic conceptual advances is the problem of control of biological activities. This problem is, of course, basic both to any full understanding of life as a whole, and to any real understanding of its most minute phenomena. Indeed, the myriad of biological activities that we can observe by direct or indirect means are all under the sway of most exquisitely precise mechanisms. Any malfunctioning of these mechanisms has serious consequences, not only for the particular function itself, but for all the related and interlinked activities."

It has been recognized for more than a thousand years that the function of the brain, like the function of the other organs of the body, is determined by its physical, chemical, and biological properties. Evidence that even its highest functions could be explained by these properties was gathered only in recent years, however; these findings, which clearly have to be confirmed by a great deal of further experimental evidence, indicate that most, if not all, of the functions of the brain are based on its bio chemical and biophysical mechanisms. This at first hearing may sound rather simple, but the ability to understand learning, emotion, perhaps even creativity, on biological terms may well be the most important scientific discovery of all time. Few pieces of knowledge can influence our future health and well-being to the degree that understanding of mental mechanisms will. It has been clearly shown in many ways in the previous volumes of this Handbook that from the biochemical or neurochemical point of view the brain is one of the most active organs. The brain seems stable and in some respects permanent; this is evidence not of inactivity but of carefully controlled homeostasis, of dynamic rather than static equilibrium, with most components undergoing metabolic alterations.

The content of Volume 8 of the Handbook of Neurochemistry is a perfect example and sample of what occupies neurochemists in the late 1980s. What occupies them are questions, concepts, and technology that either did not start with the nervous system, or rapidly moved out of its exclusivity (see, for in- stance, chapters on neurotensin, beta-lipotropin, behavioral and neurochemical effects of ACTH, cholecystokinin, etc.). Thus, the neurochemist is more and more seen as a biochemist occupied by questions, concepts, and technology that are not unique to the nervous system, even though the ultimate substrate of these questions, as well as the ultimate functions so studied and occasionally explained, are of the nervous system. Look at the case of the hypothalamic hypophysiotropic peptides, also called hypothalamic releasing factors, or hypothalamic releasing hormones. These are all small-to-medium-size polypeptides originally characterized in ex- tracts of the hypothalamus on the basis of bioassays directed at studying their effects on one or another of the secretions of the adenohypophysis. We know now that TRFs (See Chapter 8), the thyrotropin and prolactin releasing factor, somatostatin, the hypothalamic inhibitor of the secretion of growth hormone, as well as LRF, the hypothalamic decapeptide stimulating the secretion of pituitary gonadotropins, are to be found in parts of the brain other than the hypothalamus, where their function is obviously not hypophysiotropic. Such is also the case for CRF-the corticotropin and beta-endorphin releasing factor.

The second volume of the Handbook does not parallel any volume of the first edition; it is one more sign, or reflection, of the expansion of the field. By emphasizing the experimental approach, it illustrates the tools that have re cently become available for investigating the nervous system. Also, perhaps even more than other volumes, it illustrates the multidisciplinary nature of the field, requiring multidisciplinary methodology. It is now recognized that the availability of methodology is often the rate-limiting determinant of studies and that improvements or innovations in instrumentation can open up new avenues. A new improved method, although opening up new possibilities and being crucial to making advances, is only a tool whose use will determine its use fulness. If we do not recognize its possibilities, its use will be limited; if we do not recognize its limitations, it will mislead us. It is the possibilities and limitations and the results obtained that are illustrated here."

More than for any other volume of the Handbook of Neurochemistry, the chap ters in this volume on Pathological Neurochemistry deal with the interface of the laboratory bench with the patient's bedside. Most of the chapters reflect the confluence of basic scientists, clinical investigators, and physicians. Con sidered here are many of the more important disorders that afflict the nerves, muscles, spinal cord, and/or brain of mankind throughout the world. There are well over 500 such disorders. And our understanding of their nature and of measures for effective prevention or treatment depends significantly on appli cation of the biochemical disciplines that characterize neurochemistry. Before World War II, any attempt to compile a volume on pathological neurochemistry would have been largely descriptive and very rudimentary, as such "handbooks" by Hans Winterstein (1929), Irvine Page (1937), and others demonstrate. But thanks to the many major advances in research and tech nology in the postwar decades, we now stand at the threshold of understanding how to manage many of the major neurological disorders, and we may expect more such delineations in the immediate decades ahead. Neurochemistry, de fined broadly, has played a central role in this extraordinary turn of events, progressing from what J. L. W, Thudichum in 1884 called objects of anxious empiricism to his anticipation of the proud exercise of chemical precision.

This volume is concerned with metabolic reactions occurring in the nervous system. Some time ago, it was thought that since most of the intermediary metabolism that can be observed in the brain is not specific to this organ, there is little justification in studying neural metabolism as such. Later it was realized that for an understanding of neural functions, the understanding of metabolism in the brain and its alterations is essential. All aspects of the metabolism of a substrate in brain, or all metabolic reactions of the nervous system, could not be included in this volume; some will be dealt with in other volumes (such as the ones covering metabolic turn over, alterations of metabolism, or pathology). Review of the aspects covered here clearly shows that the study of metabolic reactions in the nervous system is a very active field, producing important results. As in so many areas of research, as we learn more, new aspects become known, new questions emerge, and we see that in solving some problems we open areas with many additional problems to solve. But the accomplishments to date are impressive and indicate further important advances in the future. Brain metabolism is more active, more plastic, and more comprehensive than previously estimated. It is an essential part of brain function, and with its alteration, brain function will be altered. This shows the importance of more knowledge in this area. It is hoped that this volume will be of assistance in such further studies."

Neurochemistry, having the objective of elucidating biochemical processes subserving nervous activity, emerged as an application of chemistry to the of neurobiological problems as a post-World War II phenomenon. investigation However, only in the last 40 years has the chemical community recognized neurochemistry as a distinct, if hybrid, discipline. During this period great strides have been made. However, recently neurochemistry, along with neu rophysiology, neuropharmacology, neuroanatomy, and the behavioral sci ences, has emerged to form neuroscience, a new community of scientists with its own national society, journals, and meetings. Actually, this recently formed hybrid, neuroscience, is in the process of merging with another well-established discipline, molecular genetics (frequently called molecular biology, and itself a hybrid), which appears to have sufficient hybrid vigor to form yet a new community of scientists, which, for want of a more imaginative term, has been called molecular genetic neuroscience. Clearly, advantages resulting from such mergers or hybridizations accrue not only from the merging discipline (neurochemistry in this case) to the new community (molecular genetic neuroscience), but also in the reverse direction. This Foreword will be concerned primarily with examples of this latter process."

Few can deny the paramount importance of the neurosciences, undoubtedly one of the most challenging fields in contemporary science. Recent years have witnessed the awakening of interest in brain research by many dis tinguished investigators from other branches of science, which has made possible the multidisciplinary approach needed for the complex problems of this field. The present book, which deals with one aspect of this research, is the result of the symposium held under the auspices of the New York State Research Institute for Neurochemistry and Drug Addiction in April 1968. It has become clear that brain proteins are involved in all aspects of mental function and dysfunction, and the present volume documents the latest advances in our knowledge (advances made to a large extent by con tributors to this volume). The chapters not only convey some of the enthu siasm and wonderful, cooperative spirit of the many excellent scientists ex ploring the brain, and their wealth of ideas; they also illustrate the many approaches from which cerebral proteins can be studied in a meaningful manner. In some areas even preliminary evidence is worth discussing: e.g., it is an exciting achievement that we can begin to apply the disciplines of bio chemistry to phenomena of learned behavior and information handling."

Anyone who has any contact with mental patients, old or young, or their families, or just visits a mental hospital or school for the retarded, is aware of the tremendous suffering caused by malfunctioning of the brain. The func tion of no other organ is so crucial for our everyday life, our proper func tioning, indeed our happiness, and no other illness causes as much anguish to patients or their families as mental illness. It is surprising and sad, therefore, how little effort has been devoted to research in this area; more so because such research is the only hope to ameliorate this suffering, or, to speak in the language of politics or economics, to decrease the enormous sums that we spend on trying to help our patients, with what is must generally be agreed are the most primitive and inadequate methods of treatment. Clearly, since functions of the brain are vital not only in illness, but in health, pathology is not the only area of concern to neurochemists, but it is an area that urgently needs neurochemical contributions. Progress in this field has been slower than in other areas of neurochemistry, and it seems that solutions in this field are very elusive. The reason for this is that the experimental approach is especially difficult in conditions specific for humans, or specific for complex behavior."

Researchers seeking problems that offer more hope of success often avoid subjects that seem to be difficult to approach experimentally, or subjects for which experimental results are difficult to interpret. The breakdown part of protein turnover in vivo, particularly in nervous tissue, was such a subject in the past - it was difficult to measure and difficult to explore the mechanisms involved. For factors that influence protein metabolism, it was thought that protein content, function, and distribution are controlled only by the synthetic mechanisms that can supply the needed specificity and response to stimuli. The role of breakdown was thought to be only a general metabolic digestion, elimination of excess polypeptides. We now know that the role of breakdown is much more complex: it has multiple functions, it is coupled to turnover, and it can affect protein composition, function, and synthesis. In addition to eliminating abnormal proteins, breakdown has many modulatory functions: it serves to activate and inactivate enzymes, modulate membrane function, alter receptor channel properties, affect transcription and cell cycle, form active peptides, and much more. The hydrolysis of peptide bonds often involves multiple steps, many enzymes, and cycles (such as ubiquination), and often requires the activity of enzyme complexes. Their activation, modification, and inactivation can thus play an important role in biological functions, with numerous families of proteases participating. The specific role of each remains to be elucidated.

This volume of the Handbook of Neurochemistry and Molecular Neurobiology focuses on neurochemical aspects of schizophrenia. Chapters cover the full range of schizophrenia symptoms and anatomical pathologies from neurochemical and molecular biology perspectives. Topics include changes in neurotransmitter systems, alteration in receptors, neurotransmitter release, genetic factors, protein alterations, and redox dysregulation.

This volume of the Handbook of Neurochemistry and Molecular Biology focuses on molecular events involved in synapse formation, synaptic plasticity and ongoing neural activity. The volume explores axonal growth cones, synapse development, and mechanisms of LTP and LTD, and calcium dynamics. Particular attention is given to function and trafficking of membrane proteins including various ion channels, aquaporines, gap junctions.

Understanding the biology of brain function is a great challenge and a major goal of modern science. The brain is one of the last great frontiers in science, and the unraveling of its mysteries is comparable in complexity to efforts in space exploration. A fundamental goal of neuroscience is to understand how neurons generate behavior and the pathophysiology of different mental and neurological diseases. The aim of this book is to describe recent discoveries about the basic operations of the brain and to provide an introduction to the adaptations for specific types of information processing.

Neuroimmunology is one of the most rapidly developing branches of Neurobiology, prompted by novel neurochemical, neuroendocrinological and neurophysiological investigations of the central and peripheral nervous system including neuro-endocrine systems. Neuroimmunology can be considered an interdisciplinary science that covers relevant aspects of how the peripheral immune system can influence brain physiology and elicit neuro-endocrine immuno-regulatory responses and also how local interactions between immune and neuronal mediators of the brain influence the occurrence and course of neuropathologic diseases. That explains the reason why we have in this volume chapters that focus on immune-neuro-endocrine interactions underlying the control and regulation of processes involved in both immune and brain physiology and in the pathogenesis of different nervous diseases. Among such diseases are: schizophrenia, HIV, associated dementia, rheumatoid arthritis, several experimental pathologies, multiple sclerosis, autoimmune encephalomyelitis, Theilers virus infection, nervous system demyelination diseases, the primary degenerative disorders such as Alzheimera (TM)s and Parkinsona (TM)s as well as brain injuries resulting from stroke and trauma, the neuroimmunology of gene therapy, amyotrophic lateral sclerosis, prion disease and all theoretical questions covering these pathologies. All of the above mentioned involve autoimmune processes.

It is difficult, indeed, to imagine fundamental neurobiological processes, autoimmune, neuroendocrine and infectious diseases, where immune factors are not of prime importance. The elucidation of the intimate molecular-biological problems ofimmunopathologies requires deep knowledge of the intricate connection between immunomodulators, immune competent cells of blood, brain, and other organs.

This volume contains data on multiple immunomodulators, many of which are also the products of hypothalamic brain cell neurosecretion. Interleukins (IL-1a, IL-1A, IL-2, IL-4, IL-6, TNFa), immunophylin and ubiquitin as well as proline rich peptides, comprised of 10-15 amino acids are being produced in N. Supraopticus and N. Paraventricularis and then secreted into neurohypophysis. Along the neurosecretion of the mentioned cytokines, there are other immunomodulators, the primary structure of which had been completely deciphered such as: Immunophyllins, intracellular receptors of immunosuppressors FK506, cyclosporine A., rapamicin. They are peptidyl-prolyl-cis-trans-isomerases. There are novel immunological hypothalamic factors such as ubiquitin, macrophage migration inhibitory factor (MIF), as well as Thymosin A 4(1-39). This data allowed us to propose the concept of neuroendocrine immune system of the brain.

Stroke is a global health problem affecting approximately 15 million people annually in the world and about 700,000 in the United States. It is the third leading cause of death and the most common cause of disability in most developed countries.

Acute Ischemic Injury and Repair in the Nervous System is intended to provide the most up-to-date knowledge of the mechanisms of neuronal death and repair after stroke. It is our belief that this volume of the Handbook of Neurochemistry and Molecular Neurobiology provides an excellent review of the tremendous advances of the past decades in the neurochemical and molecular biological aspects of cerebral ischemia. It is hoped that these advances will provide an impetus for basic scientists and clinicians to further their translational research and to promote the insights for development of therapeutic interventions for stroke.

Researchers seeking problems that offer more hope of success often avoid subjects that seem to be difficult to approach experimentally, or subjects for which experimental results are difficult to interpret. The breakdown part of protein turnover in vivo, particularly in nervous tissue, was such a subject in the past - it was difficult to measure and difficult to explore the mechanisms involved. For factors that influence protein metabolism, it was thought that protein content, function, and distribution are controlled only by the synthetic mechanisms that can supply the needed specificity and response to stimuli. The role of breakdown was thought to be only a general metabolic digestion, elimination of excess polypeptides. We now know that the role of breakdown is much more complex: it has multiple functions, it is coupled to turnover, and it can affect protein composition, function, and synthesis. In addition to eliminating abnormal proteins, breakdown has many modulatory functions: it serves to activate and inactivate enzymes, modulate membrane function, alter receptor channel properties, affect transcription and cell cycle, form active peptides, and much more. The hydrolysis of peptide bonds often involves multiple steps, many enzymes, and cycles (such as ubiquination), and often requires the activity of enzyme complexes. Their activation, modification, and inactivation can thus play an important role in biological functions, with numerous families of proteases participating. The specific role of each remains to be elucidated.