Molecular and Cellular Mechanisms of Neuronal Plasticity: Basic and Clinical Implications

228 Pages·1998·17.077 MB·English

by  Daniel L. Alkon (auth.), Yigal H. Ehrlich (eds.)

MOLECULAR AND
CELLULAR MECHANISMS
OF NEURONAL PLASTICITY
Basic and Clinical Implications
ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY
Editorial Board:
NATHAN BACK, State University of New York at Buffalo
IRUN R. COHEN, The Weizmann Institute of Science
DAVID KRITCHEVSKY, Wistar Institute
ABEL LAJTHA, N. S. Kline institute lor Psychiatric Research
RODOLFO PAOLETTI, Universily ofMilQIl
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MOLECULAR AND
CELLULAR MECHANISMS
OF NEURONAL PLASTICITY
Basic and Clinical Implications
Edited by
Yigal H. Ehrlich
The College of Staten Island ofThe City University of New York, and
The CSIIIBR Center for Developmental Neuroscience
Staten Island, New York, and
The City University Graduate School
New York, New York
SPRINGER SCIENCE+BUSINESS MEDIA, LLC
Llbrary of Congress Cataloglng-In-Publlcatlon Data
Molecular and cellular mechanlsas of neuronal plasticity , basic and
cllnical lmpllcatlons 1 edlted by Vlgal H. Ehrllch.
p. c •. -- (Advances in experimental aedicine and biology : v.
446)
"Proceedings of the Neurosclence SymposiuM on Molecular and
Cellular Mechanisms of Neuronal Plasticlty. held Oecember 4. 1996.
in Staten Is~and, New Vork"--T.p. verso.
Includes bibliographical references and index.
ISBN 978-1-4613-7209-7 ISBN 978-1-4615-4869-0 (eBook)
DOI 10.1007/978-1-4615-4869-0
1. Neuroplastlcity--Congresses. 2. Molecular neurobiology
-Congresses. 3. Neurons--Congresses. 1. Ehrllch, Vlgal H.
II. Neurosclence Syaposlum an Molecular and Cellular Mechanlsms of
Neuronal Plastlclty (1996 , Staten Island. New York. N.V.l
III. Ser Ies.
[ONLM, 1. Neuronal Plasticlty--physlology congresses. 2. Neurons
-physlology congresses. Hl A0559 v.446 19961
QP363.3.M65 1996
61 l' .0166--dc21
ONLM/OLC
for Llbrary of Congress 96-31763
CIP
Proceedings of the Neuroscience Symposium on Molecular and Cel\ular Mechanisms of Neuronal Plasticity,
held Oecember 4, 1996, in Staten Island, New York, with chapters written by symposium speakers and
additional invited authors during 1997 and updated through March 1998.
ISBN 978-1-4613-7209-7
© 1998 Springer Science+Business Media New York
Originally published by Kluwer Academic / Plenum Publishers in 1998
Softcover reprint of the hardcover 1s t edition 1998
AII 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
PREFACE
Cells in the nervous system have the capability of undergoing extremely long-lasting
alterations in response to hormonal, pharmacological and environmental stimulations. The
mechanisms underlying this neuronal plasticity are activated by experiential inputs and
operate in the process of learning and the formation of memories in the brain. Numerous
studies have proven the biological basis of memory formation and have begun to identify
the biochemical traces and cellular circuits that are formed by experience, and which par
ticipate in the storage of information in the brain, its retention for long durations, and its
retrieval upon demand. Furthermore, the elucidation of molecular and cellular mecha
nisms operating in the adaptive processes which underlie neuronal plasticity have begun
to yield novel strategies in the diagnosis and treatment of neurological diseases and neuro
phychiatric disorders. A major practical outcome of these investigations has been the
emergence of a new generation of therapeutic agents; memory enhancing drugs developed
on the basis of understanding the biochemistry, cellular biology and molecular genetics of
processes underlying neuronal plasticity. These studies are at the focus of the present Vol
ume, which has emerged initially from a Symposium held at the College of Staten Island
of The City University of New York on December 4, 1996. This Volume includes contribu
tions submitted during 1997 and early 1998 by presenting speakers of the Symposium, as
well as additional invited authors who conduct unique studies in this area. As in my pre
vious editorial work (Ehrlich et aI., Volume 116 and Volume 221 of Advances in Experi
mental Medicine and Biology, Plenum Press, New York), I hope that the readers will find
here a useful source of information and ideas for stimulating studies which will serve to
further narrow the gap between basic neuroscience research and its clinical implications.
One of the guidelines in selecting the contributions invited as chapters for this Vol
ume has been the presentation of research areas that have not been highlighted in previous
books on this topic. Thus, in addition to studies on the involvement of functional proteins
(enzymes, receptors) in neuronal adaptation, this Volume presents recent developments on
the critical roles of bioactive lipids and nucleotides in these processes. In addition to the
widely studied role of second messengers-regulated protein kinases in mechanisms under
lying neuronal plasticity, a review of studies on extracellular protein phosphorylation sys
tems operating on the surface of brain neurons is presented in this Volume. Together with
studies of mammalian brain, the advantages of investigating avian hippocampus as a
model to study synaptic plasticity is presented here. While the NMDA sub-type of gluta
mate receptors has been a major focus of studies on hippocampal synaptic plasticity, a
chapter on the clinical impact of studies on the role of metabotropic glutamate receptors in
v
Preface
the plasticity of excitatory responses in the hippocampus is presented here as a bridge be
tween the two sections of the Volume. The first section presents studies of basic mecha
nisms operating in a wide-range of adaptive processes. These include synaptic changes
responsible for associative memory, long-term habituation, long-term potentiation, neuro
nal development and programmed neuronal cell-death (apoptosis). The second section of
this Volume, beginning with Chapter 9, presents recent advances in investigations that
have demonstrated the clinical implications of this research. These include: state-of-the-art
use of transgenic models in studies of molecular and cellular mechanisms implicated in fa
milial Alzheimer's disease and Amyotropic Lateral Sclerosis (ALS); studies of specific
proteins implicated in Alzheimer's disease-including an adapter that binds to the l3-amy
loid precursor protein (I3-APP) and the microtubular protein Tau and its membrane-bound
counterpart. The advantages of using cell culture models for elucidating the causes of
neuronal degeneration and for identifying mechanisms of neuroprotection are also pre
sented among the chapters in the section on Clinical Implications.
The Editor wishes to express here his thanks to a few of the many individuals who
contributed to the organization of the Symposium: the President of the College of Staten
Island (CSI) Dr. Marlene Springer and the Vice-President for Academic Affairs and Pro
vost Dr. Mirella Affron, the Director of the New York State Institute of Basic Research in
Developmental Disabilities (lBR) Dr. Henryk M. Wisniewski, the Deputy Director of the
CSI/IBR Center for Developmental Neuroscience Dr. E. Trenkner, and the Dean of Sci
ence at CSI Dr. Martin Zeldin. Special thanks are due to the staff of the Center for Per
forming Arts of CSI, and in particular to the secretary of the Program in Neuroscience of
CSI, Rosa Shirippa for her tireless efforts. Finally, the support and help of my colleague
and friend Dr. Elizabeth Kornecki in the preparation of this Volume is acknowledged with
affection and admiration.
Yigal H. Ehrlich
CONTENTS
I. Molecular Specificity of Synaptic Changes Responsible for Associative Memory
Daniel L. Alkon
2. Behavioral and Mechanistic Bases of Long-Term Habituation in the Crab
Chasmagnathus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Daniel Tomsic, Arturo Romano, and Hector Maldonado
3. Bioactive Lipids and Gene Expression in Neuronal Plasticity 37
Nicolas G. Bazan
4. Surface Protein Phosphorylation by Ecto-Protein Kinases: Role in Neuronal
Development and Synaptic Plasticity ... . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
Yigal H. Ehrlich, Michael V. Hogan, Zofia Pawlowska, Andrzej Wieraszko,
Ethel Katz, Tomasz Sobocki, Anna Babinska, and Elizabeth Komecki
5. Extracellular ATP-Induced Apoptosis in PC12 Cells. . . . . . . . . . . . . . . . . . . . . . . 73
Albert Y. Sun and Yong-Mei Chen
6. The Role of the Neural Growth Associated Protein B-50/Gap-43 in
Morphogenesis ............................................... 85
L. H. J. Aarts, P. Schotman, J. Verhaagen, L. H. Schrama, and W. H. Gispen
7. Avian Hippocampus as a Model to Study Spatial Orientation-Related Synaptic
Plasticity .................................................... 107
Andrzej Wieraszko
8. Metabotropic Glutamate Receptors in the Plasticity of Excitatory Responses in
the Hippocampus: Clinical Impact ................................ 13 I
Lisa R. Merlin
9. Familial Amyotrophic Lateral Sclerosis and Alzheimers Disease: Transgenic
Models...................................................... 145
Philip C. Wong, David R. Borchelt, Michael K. Lee, Carlos A. Pardo,
Gopal Thinakaran, Lee J. Martin, Sangram S. Sisodia, and Donald L. Price
vii
viii Contents
10. Proteins Implicated in Alzheimer Disease: The Role ofFE65, a New Adapter
which Binds to ~-Amyloid Precursor Protein ....................... 161
Kira S. Ermekova, Alex Chang, Nicola Zambrano,
Paola de Candia,Tommaso Russo, and Marius Sudol
11. Influence of Phospholipids and Sequential Kinase Activities on Tau in Vitro 181
Thomas B. Shea and Fatma 1. Ekinci
12. Cell Culture Models of Neuronal Degeneration and Neuroprotection:
Implications for Parkinson's Disease .............................. 203
Efthimia T. Kokotos Leonardi and Catherine Mytilineou
13. Aging and Dementia of the Alzheimer Type: In Persons with Mental Retardation 223
Henryk M. Wisniewski and Wayne Silverman
Index 227
1
MOLECULAR SPECIFICITY OF SYNAPTIC
CHANGES RESPONSIBLE FOR ASSOCIATIVE
MEMORY
Daniel L. Alkon
Laboratory of Adaptive Systems
NINDS, NIH
Bethesda, Maryland
INTRODUCTION
Specificity of molecular mechanisms for synaptic weight regulation is critical for
understanding the cellular basis of learning and memory. Thus, while we have known for
decades that protein synthesis is involved in long-term memory (Flexner et aI., 1963; Hy
den et aI., 1965; Agranoff et aI., 1966; Matthies, 1989; Van der Zee et aI., 1992; Nelson
and Alkon, 1992; see Kandel, this volume), protein synthesis is also necessary for so many
cellular functions that its direct contribution to memory function remains obscure. Here,
however, we describe a new signalling protein, Calexcitin, which powerfully and specifi
cally regulates synaptic weight as well as synaptic sign and is activated by a molecular
cascade more directly implicated in associative learning of diverse molluscan and mam
malian species. This cascade begins when temporally related training stimuli (e.g. an
auditory tone and a touch stimulus to the cornea) elicit temporally related synaptic signals
that in turn elicit temporally related second messengers such as Ca++, DAG (diacyl
glycerol), and AA (arachidonic acid). Temporally associated second messengers activate
protein kinase C (PKC) through its translocation to the inner surface of neuronal mem
branes (and possibly membranes of subcellular organelles such as the ER). Membrane-as
sociated PKC, now sensitive to low levels of Ca -+ (0.1-1.0 uM), phosphorylates critical
signaling proteins such as the recently sequenced cp20 (now called "Calexcitin"), the first
known protein to bind both Ca++ and GTP. Calexcitin, shown to be a high affinity substrate
of Ca++-dependent isozymes of PKC (particularly the a-isozyme), when phosphorylated
during learning, also becomes membrane associated and inactivates voltage-dependent K+
channels (such as lA' Ie. etc.). Recent experiments (Weh et aI., in press) also implicate Cal
excitin in the regulation of Ca++ release from the endoplasmic reticulum and thus further
CaH-mediated transformations of synaptic weight and perhaps structure. Still other recent
experiments (Cavallero et aI., Soc.for Neuroscience, Abstract, in press) showed increased
Molecular and Cellular Mechanisms of Neuronal Plasticity, edited by
Ehrlich. Plenum Press. New York, 1998.
2 D. L. Alkon
activation of the gene responsible for ryanodine receptor expression after spatial maze
learning.
Through this molecular cascade, stimuli associated during training increase dendritic
excitability and thus increase synaptic weight through enhanced post-synaptic responsive
ness, as demonstrated for associative memory within the molluscan (Hermissenda) visual
vestibular network. the hippocampus. and the H6 cerebellar cortex. In more recent studies,
Calexcitin was found to markedly enhance synaptic EPSP's and to inactivate IPSP's.
These mechanisms of memory storage induced in vivo show some convergence with in vi
tro models of cellular memory (e.g LTP, LTD, LTT Long-term synaptic transformation-see
below) such as involvement of PKC activation. One divergence, however, was confirmed
when antisense oligonucleotides to mRNA that codes for mkvl.l in vivo eliminated mem
ory retention (Meiri et a!., in press) along with specific voltage-dependent K+ channels,
but leaving LTP unimpaired. These conserved molecular and biophysical mechanisms that
can regulate synaptic weight during associative memory have also recently been impli
cated as targets of pathophysiology induced by nM levels of soluble l3-amyloid in the
clinical entity Alzheimer's Disease, recognized by its memory deficits.
SYNAPTIC TRANSFORMATIONS DURING ASSOCIATIVE
LEARNING
In vitro changes of synaptic efficacy in fully differentiated nervous systems have been
known and analyzed since Feng first identified post-tetanic potentiation at the neuromuscu
lar junction in the late 1930's. Since that time, many additional examples of synaptic effi
cacy modification have been identified in diverse species (Katz, 1966; Kuffler et aI., 1984).
These include synaptic facilitation at the lobster and crab neuromuscular junctions, hetero
synaptic facilitation in the mollusc abdominal ganglion, long-term potentiation (LTP) of
glutamatergic EPSP's recorded from pyramidal cells in the rat hippocampus, and long-term
depression (LTD) of glutamatergic EPSP's recorded from Purkinje cells of the rat cerebel
lum. All of these changes of synaptic efficacy are candidates for synaptic mechanisms pos
tulated by such pioneers as Cajal, Sherrington, and Pavlov to provide a physiologic basis for
memory. Yet, these examples of synaptic modification have been difficult to observe during
associative learning and memory behavior of living animals.
To assess in vitro synaptic change(s) in the context of in vivo associative learning
and memory, LAS scientists set out many years ago to correlate synaptic changes of effi
cacy with behavioral acquisition and retention of associative memory. Pavlovian condi
tioning of the mollusc Hermissenda (Alkon, 1983). for example, produced long-term
enhancement of type B cell excitability (and thus responsiveness) and thereby enhanced
input to and output from downstream motor neurons. Pavlovian conditioning of the rabbit
(Thompson. 1986) was shown in LAS studies to enhance post-synaptic dendritic excitabil
ity and the amplitude of summated EPSP responses of CA I pyramidal cells (Disterhoft et
aI., 1986; Lo Turco et al., \985). Still other LAS studies (Schreurs et al.. 1997) demon
strated intradendritic excitability increases in cerebellar microzones after rabbit Pavlovian
conditioning (Figure I). All of these examples correlated with and/or could be accounted
for by long-term inactivation of voltage-dependent K+ channels (as explained below) and
are consistent with current understanding of ion channel distribution within the pyramidal
cell dendritic tree (Migliore et a!., 1995). A crucial part of this past research was accom
plished when LAS investigators pioneered the analysis of cellular changes within brain
slices taken from trained and control animals exposed to a variety of stimulus paradigms.