Alterations of Metabolites in the Nervous System

613 Pages·1985·22.613 MB·English

by  L. Austin (auth.), Abel Lajtha (eds.)

Vol. 9
Abel Lajtha E ditior
Handbook of
Neurochemistry
Second Edition
Handbook of
Neurochemistry
SECOND EDITION
Volume 9
ALTERATIONS OF
METABOLITES IN
THE NERVOUS SYSTEM
Handbook of
Neurochemistry
SECOND EDITION
Edited by Abel Lajtha
Center for Neurochemistry, Wards Island, New York
Volume 1 • CHEMICAL AND CELLULAR ARCHITECTURE
Volume 2 • EXPERIMENTAL NEUROCHEMISTRY
Volume 3 • METABOLISM IN THE NERVOUS SYSTEM
Volume 4 • ENZYMES IN THE NERVOUS SYSTEM
Volume 5 • METABOLIC TURNOVER IN THE NERVOUS SYSTEM
Volume 6 • RECEPTORS IN THE NERVOUS SYSTEM
Volume 7 ·STRUCTURAL ELEMENTS OF THE NERVOUS SYSTEM
Volume 8 • NEUROCHEMICAL SYSTEMS
Volume 9 ·ALTERATIONS OF METABOLITES IN THE NERVOUS
SYSTEM
Volume 10 • PATHOLOGICAL NEUROCHEMISTRY
Handbook of
Neurochemistry
SECOND EDITION
Volume 9
ALTERATIONS OF
METABOLITES IN
THE NERVOUS SYSTEM
Edited by
Abel Lajtha
Center for Neurochemistry
Wards Island, New York
SPRINGER SCIENCE+BUSINESS MEDIA, LLC
Library of Congress Cataloging in Publication Data
Main entry under title:
Handbook of neurochemistry.
Includes bibliographical references and index.
Contents: v. I. Chemical and cellular architecture-[etc.]-v. 7. Structural elements
of the nervous system- -v. 9. Alterations of metabolites in the nervous system.
I. Neurochemistry-Handbooks, manuals, etc. I. Lajtha, Abel. [DNLM: I.
Neurochemistry. WL 104 H434]
QP356.3.H36 1982 612'.814 82-493
ISBN 978-1-4757-6742-1 ISBN 978-1-4757-6740-7 (eBook)
DOI 10.1007/978-1-4757-6740-7
© 1985 Springer Science+Business Media New York
Originally published by Plenum Press, New York in 1985
All rights reserved
No part of this book may be reproduced, stored in a retrieval system, or transmitted
in any form or by any means, electronic, mechanical, photocopying, microfilming,
recording, or otherwise, without written permission from the Publisher
Contributors
L. Austin, Department of Biochemistry, Monash University, Clayton 3168,
Victoria, Australia
Sze-Chuh Cheng, Department of Anesthesia, Northwestern University Medical
School, Chicago, Illinois 60611
Doris H. Clouet, New York State Division of Substance Abuse Services, Test
ing and Research Laboratory, and Department of,Psychiatry, SUNY Down
state Medical School, Brooklyn, New York 11217
Joseph T. Coyle, Division of Child Psychiatry and Departments of Psychiatry,
Neuroscience, Pharmacology, and Pediatrics, The Johns Hopkins University
School of Medicine, Baltimore, Maryland 21205
Larry H. Dashefsky, Department of Neurology, Yale University School of
Medicine, New Haven, Connecticut 06510
Robert J. DeLorenzo, Department of Neurology, Yale University School of
Medicine, New Haven, Connecticut 06510
Laurie L. Foudin, Sinclair Comparative Medicine Research Farm and Bio
chemistry Department, University of Missouri, Columbia, Missouri 65201
Martin Frizell, Departments of Neuropathology and Ophthalmology, Sahl
gren's Hospital, S-413 45 Goteborg, Sweden
Samuel Gershon, Lafayette Clinic and Department of Psychiatry, Wayne State
University School of Medicine, Detroit, Michigan 48201
Paul J. Goodnick, Department of Lithium Studies, New York State Psychiatric
Institute, New York, New York 10032
Marian W. Kies, Section on Myelin Chemistry, Laboratory of Cerebral Me
tabolism, National Institute of Mental Health, Bethesda, Maryland 20205
Arnulf H. Koeppen, Neurology Service, Veterans Administration Medical Cen
ter, and Department of Neurology, Albany Medical College, Albany, New
York 12208
J. E. Leysen, Department of Biochemical Pharmacology, Janssen Pharmaceu
tica, B-2340 Beerse, Belgium
W. Graham McLean, Department of Pharmacology and Therapeutics, Uni
versity of Liverpool, Liverpool L69 3BX, England
Matthew S. Miller, Institute of Neurotoxicology, Albert Einstein College of
Medicine, Bronx, New York 10461
v
vi Contributors
Edwin M. Nemoto, Anesthesia and CCM Research Laboratories, Department
of Anesthesiology and Critical Care Medicine, University of Pittsburgh
School of Medicine, Pittsburgh, Pennsylvania 15261
C. J. E. Niemegeers, Department of Pharmacology, Janssen Pharmaceutica,
B-2340 Beerse, Belgium
Sidney Roberts, Department of Biological Chemistry, School of Medicine, and
the Brain Research Institute, UCLA Center for the Health Sciences, Los
Angeles, California 90024
Stephen M. Ross, Institute of Neurotoxicology, Albert Einstein College of
Medicine, Bronx, New York 10461
Mohammad I. Sabri, Institute of Neurotoxicology, Albert Einstein College of
Medicine, Bronx, New York 10461
Bradley W. Schwab, Institute of Neurotoxicology, Albert Einstein College of
Medicine, Bronx, New York 10461. Present address: Department of En
vironmental and Industrial Health, School of Public Health, University of
Michigan, Ann Arbor, Michigan 48109
Henry Sershen, Center for Neurochemistry, The Nathan S. Kline Institute for
Psychiatric Research, Wards Island, New York 10035
Johan Sjostrand, Departments of Neuropathology and Ophthalmology, Sahl
gren's Hospital, S-413 45, Goteborg, Sweden
Marian Edmonds Smith, Department of Neurology, Veterans Administration
Medical Center, Palo Alto, California 94304; and Stanford University School
of Medicine, Stanford, California 94305
John R. Smythies, Department of Psychiatry and Neurosciences Program, Uni
versity of Alabama in Birmingham, Birmingham, Alabama 35294
PeterS. Spencer, Institute of Neurotoxicology, Albert Einstein College of Med
icine, Bronx, New York 10461
Edward M. Stricker, Department of Psychology, University of Pittsburgh, Pitts
burgh, Pennsylvania 15260
Albert Y. Sun, Sinclair Comparative Medicine Research Farm and Biochem
istry Department, University of Missouri, Columbia, Missouri 65201
Grace Y. Sun, Sinclair Comparative Medicine Research Farm and Biochem
istry Department, Univeristy of Missouri, Columbia, Missouri 65201
Igor A. Sytinsky, Leningrad State University, 191025 Leningrad, USSR
Sujata Tewari, Alcohol Research Center, Department of Psychiatry and Human
Behavior, University of California, Irvine, California 92717
Stephen Zamenhof, Mental Retardation Research Center, and Brain Research
Institute, UCLA School of Medicine, Los Angeles, California 90024
Michael 1. Zigmond, Department of Biological Sciences, University of Pitts
burgh, Pittsburgh, Pennsylvania 15260
Foreword
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.
The history of chemical work on GABA goes back 35 years and it recapitulates
most of the modern history of neurochemical endeavor. At the time that GABA
was discovered in brain and the first experiments were being performed on its
biochemistry and pharmacology, an accepted approach to neurochemistry was
to study the whole brain or some grossly defined regions. Acetone powders,
homogenates, slices, and other types of preparations were made from whole
rodent brain and the projected studies were performed on such preparations.
In due course, it became possible to analyze for the components of the GABA
system in different brain regions, and laminar analyses were performed on such
layered structures as the cerebellum, hippocampus, retina, and superior col
liculus. Although the functions of most brain regions in terms of physiology,
morphology, and behavior still were not well understood, a certain degree of
definition was attained relevant to quantitative aspects of the amounts ofGABA
and the enzymes most importantly involved in its formation and degradation,
GAD and GABA transaminase (GABA-T). The localization of GABA neurons
was inferred by correlating microchemical, electrophysiological, pharmaco-
vii
viii Foreword
logical, and iontophoretic studies with what was known of the cytoarchitecture
of specific regions of brain and spinal cord. Analyses of GABA contents and
GAD activities were performed in almost all identifiable brain structures and
spinal cord. Some studies combined biochemical analyses with various types
of lesioning procedures in an attempt to correlate specific neural degenerations
with losses of GAD and GABA. The distributions of the components of the
GABA system also were studied extensively by subcellular fractionation tech
niques in preparations from whole brain or selected regions. Interpretation of
results from above types of analyses always suffered from lack of definition,
attributable to the presence of millions of cells of different types in any dissected
region, and definitive conclusions were not possible about specific synaptic
connections. Even when individual cell bodies of large neurons (e.g., Purkinje
cells) were dissected out and subjected to microanalytical examination, pre
synaptic endings from the axons of other neurons adhered to the neuronal
somata, and it was impossible to estimate the proportions of a particular mea
sured variable contributed by somata or presynaptic endings. Exquisite dissec
tion techniques eventually made possible the determination of GABA contents
in membrane-containing and membrane-free portions of individual Deiters'
neurons. However, none of the above approaches clarified the manner in which
GABA neurons might participate in information processing in different parts
of the vertebrate CNS.
A critical examination of our own work and that of others led to the in
evitable conclusion that direct visualization of components of the GABA system,
particularly GABA neurons and their terminals, was necessary to obtain un
equivocal proof of the existence of components of the GABA system at specific
synaptic sites in neural tissues. The most likely approaches to achieve this goal
appeared to be those that might lead to visualization of the pertinent proteins
(GAD, GABA transaminase (GABA-T), and the GABA transport and receptor
proteins) at the light and electron microscopic levels. Early in 1968 I decided
with great trepidation to "go for broke," so to speak, and to begin with GAD,
the rate-limiting enzyme in GABA formation, that was known to be present in
an easily solubilized form and in high concentration in synaptosomes. We first
made attempts to develop chemical procedures for the visualization of GAD,
but all failed because of the difficulties in demonstrating histochemically the
products of the enzymatic reaction, GABA and COz. The difficult alternative
approach was to locate GABA neurons by immunocytochemical procedures.
This required the preparation of pure GAD from brain, development of anti
bodies to the enzyme, and then visualization of the antibodies by a suitable
labeling technique specifically at those cellular and subcellular sites where
GAD, the antigen, is located. It is to this task that we have, in part, dedicated
ourselves for the past 16 years.
The first step was the preparation of pure GAD. After some false starts,
we succeeded in obtaining a homogeneous preparation of GAD from a lysate
of a crude mitochondrial preparation from mouse brain. Mouse brain was used
as a starting material because the GAD activity per unit of protein of whole
mouse brain is several times higher than that from other species and because
we wanted eventually to develop an antiserum applicable to visualization of
Foreword ix
the enzyme in rodent tissues. A number of subsequent studies dealt with chem
ical and immunological properties of GAD. It was ascertained that a specific
precipitin band could be obtained with rabbit antiserum to purified mouse brain
GAD, and this was sufficient for us to employ immunocytochemical procedures
for localization of the enzyme. To my knowledge, this was the first time that
immunocytochemical visualization of a brain neurotransmitter-forming enzyme
was attempted or achieved.
It has taken more than thirty years of work to move from an unknown
ninhydrin-reactive spot on a two-dimensional paper chromatogram of an extract
of mouse brain to the establishment of GABA as a major inhibitory transmitter
and to the visualization of GABA-releasing neurons in nervous system struc
tures and the establishment of the beginnings of a rational pharmacology of the
GABA system. Even this relatively modest degree of progress has been pos
sible only because of the participation in these studies of scientists from the
several pertinent disciplines the world over. The recent coalescence of these
separate disciplines into the single one of "neurosciences" has made it possible
for us to begin to share techniques, vocabularies, and outlooks. And yet, there
is a sense of uneasiness among us. Who can master all of the pertinent facts
and technologies, or even keep up with a small portion of the literature? Will
we be drowned by the sea of observations before we will be able to recognize
the forest for the trees and devise the master plans of nervous system function?
I believe that one must strive constantly to establish valid core positions from
which to view meaningfully both phenomena of major human interest such as
memory, consciousness, various aspects of normal and abnormal behavior,
aging, etc., and the molecular and submolecular events that constantly are
taking place at the level of excitable membranes.
My current working models of nervous system function are based partly
on many experimental observations, often supported by our extensive im
munocytochemical findings, and partly on their extrapolation into reasonable
potentialities. Particular emphasis is placed on consideration of the roles of
inhibitory GABAergic neurons in normal and abnormal information processing
in the CNS. The point .of view taken is that the nervous system is highly re
strained, with inhibitory neurons acting like reins that serve to keep the neu
ronal "horses" from running away. I proposed that in behavioral sequences,
innate or learned, preprogrammed circuits are released to function at varying
rates and in various combinations. This is accomplished largely by the disin
hibition of pacemaker neurons whose activities are under the control of toni
cally active inhibitory command neurons, many of which use GABA as a trans
mitter. According to this view, disinhibition is permissive, and excitatory input
to pacemaker neurons has mainly a modulatory role. In addition to the above
restraining function, local circuit GABAergic neurons participate in processes
that result in producing feedforward, feedback, surround, and presynaptic in
hibition and presynaptic facilitation. Information arriving from several sources
is integrated in specialized command centers such as the cerebellar cortex, the
basal ganglia, and the reticular nucleus of the thalamus which, through inhib
itory GABAergic neurons, exert high frequency monosynaptic tonic inhibition
in various brain regions. The analysis of the inputs to the command regions is