Synaptic Plasticity
NEUROLOGICAL DISEASE AND THERAPY Advisory Board
Louis R. Caplan, M.D.
Professor of Neurology Harvard University School of Medicine
Beth Israel Deaconess Medical Center Boston, Massachusetts
William C. Koller, M.D.
Mount Sinai School of Medicine New York, New York
John C. Morris, M.D.
Friedman Professor of Neurology Co-Director, Alzheimer’s Disease Research Center
Washington University School of Medicine St. Louis, Missouri
Bruce Ransom, M.D., Ph.D.
Warren Magnuson Professor Chair, Department of Neurology University of Washington School of Medicine
Seattle, Washington
Kapil Sethi, M.D.
Professor of Neurology Director, Movement Disorders Program
Medical College of Georgia Augusta, Georgia
Mark Tuszynski, M.D., Ph.D.
Associate Professor of Neurosciences Director, Center for Neural Repair University of California–San Diego
La Jolla, California
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69. Synaptic Plasticity : Basic Mechanisms to Clinical Applications, edited by Michel Baudry, Xiaoning Bi, and Steven S. Schreiber
70. Handbook of Essential Tremor and Other Tremor Disorders, edited by Kelly E. Lyons and Rajesh Pahwa
Synaptic Plasticity
Basic Mechanisms to Clinical Applications
edited by
Michel Baudry Xiaoning Bi
Steven S. Schreiber
Boca Raton London New York Singapore
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Although tremendous progress has been made over the last decade in our understanding of the molecular and cellular mechanisms underlying synaptic plasticity, this term has been so widely used that it has lost most of its original meaning. The editors of this book use this term to refer to fundamental processes that are responsible for adaptive properties of the central nervous system (CNS) under phy- siological as well as pathological conditions. Thus, many mechanisms regarding the way physical and nervous activ- ity, diseases, and insults regulate synaptic transmission in the adult CNS have been characterized, and this under- standing has started to be implemented in the design of new treatments for neuronal diseases and age-related loss of cognitive function. Likewise, basic processes used by developing nervous systems to establish their adult patterns of connectivity have been described in exquisite detail. In particular, the roles of growth factors and their effects on gene regulation are leading the way to new avenues for the treatment of several genetic and environmental defects associated with the inappropriate establishment of neuronal
iii
connectivity. Furthermore, the field of neuronal degenera- tion has seen a renewed excitement with advances in stem cell research.
At the other end of the spectrum of scientists interested in improving alterations in various CNS functions, neurolo- gists, neurosurgeons, occupational therapists, and other care- givers are developing new approaches to help patients recover lost functions using the very same principles of synaptic plasticity studied by molecular and cellular neurobiologists.
In particular, several methods of rehabilitation therapy and repair are in various stages of implementation. The premise here is that the plastic, adaptive properties of neuronal net- works will allow for compensatory mechanisms in a way that might provide new functionalities to replace damaged circui- tries. Furthermore, the use of genetically engineered cells or neurons targeted at specific locations or for specific functions might well facilitate recovery of lost functions.
A third category of scientists interested in brain repair is slowly emerging out of the new disciplines of neural engi- neering and neural computation. Their explicit goals are to use principles extracted from neurobiological systems to reverse engineer neuronal circuits that are damaged as a result of genetic defect, trauma, and other disease processes.
This requires not only a detailed description of neuronal cir- cuitries in various CNS structures as well as the rules reg- ulating synaptic transmission and activity-dependent changes in synaptic transmission, but also the ability to implement neuronal circuits and rules of plasticity into silicon-based circuits and devices. In addition, this approach will require new technologies to permit long-term interac- tions between silicon-based devices and neural tissues.
We reasoned that the time was ripe for presenting a sum- mary of the most recent advances in these three lines of research. Each of them has progressed along paths that superficially look quite different, but nevertheless they all are converging toward the same fundamental goal; that is, to provide new therapeutics for alleviating impairments of CNS function resulting from gene defects, injury, or disease.
Clearly, some of the research is years away from providing
any concrete device or treatment, but technological as well as empirical advances move so fast that it is not too early to think about the clinical and ethical applications of these lines of work. Similarly, gene therapy was thought to remain for years in an incubation phase, but advances in this field have been so rapid that ethical concerns as well as practical issues have now moved to the front stage of the discussion. Because of the apparent distance between these fields, they are rarely associated in books, and this was another incentive for us to bring together leaders in these fields to provide their views, ideas, and suggestions for future directions. The book is there- fore organized in sections that reflect the three approaches mentioned above.
The first section is devoted to basic mechanisms of synap-
tic plasticity and is subdivided into two sections. The first sec-
tion reviews various forms of plasticity in synaptic and
nonsynaptic transmission. In particular, one of us (MB) pro-
vides an update on the mechanism of long-term potentiation
(LTP) and on the development of a new class of molecules,
the ampakines (positive modulators of AMPA receptors),
which are making their way to the clinic for various indica-
tions, including mild-cognitive impairment associated with
aging. The group of Dominique Muller presents convincing
evidence that neural activity-induced plasticity is associated
with formation of new synapses. On the other hand, Bach-y-
Rita reminds us that nonsynaptic transmission, also called
volume transmission, plays an important role in the brain
under physiological and pathological conditions and that it
may play a very significant role in tactile vestibular substitu-
tion following bilateral vestibular damage. The second section
deals with various factors that participate in mechanisms reg-
ulating neuronal sprouting after lesions, age-related neurode-
generation, and exercise-induced improvement of cognitive
function. One of us (XB) reviews the role of lysosomal dys-
function in aging and presents an hypothesis linking dysfunc-
tion in this cellular system to impairment in trophic
signaling. The group of Marie-Francoise Chesselet sum-
marizes the evidence that axonal sprouting is much more
widespread than initially thought and discusses potential
mechanisms underlying this phenomenon. Gomez-Pinilla and one of his associates provide an extensive review of the char- acteristics and potential functions of neurotrophins, and in particular, brain-derived neurotrophic factor (BDNF). They then illustrate how the understanding of these functions could be translated into new ways to stimulate brain function and the potential therapeutic benefits of exercise, enriched environment, or diet. Finally, Roberta Brinton takes the diffi- cult task of explaining the recent failures of estrogen therapy for the treatment or prevention of Alzheimer’s disease. She identifies potential factors that could account for these fail- ures and proposes a new framework to understand the mechanisms of estrogen action.
The second section of the book is directed at clinical appli- cations of synaptic plasticity processes and is subdivided into three sections. The first one deals with various aspects of injury. Kornblum’s group describes the advantages of using imaging techniques and in particular, positron emission tomo- graphy (PET), to evaluate the role of neural plasticity in recov- ery from damage in rodent models of brain injury. Jim Simpkins and colleagues review the current evidence support- ing neuroprotective roles for estrogens in stroke and also dis- cuss the argument for the use of estrogen as a neuroprotectant for Alzheimer’s disease. Finally, one of us (SS) describes the current knowledge of the mechanisms underlying neuronal death, summarizes the evidence supporting a role for apopto- tic cell death in spinal cord injury and outlines potential approaches to interfere with these processes following spinal cord injury. The second part of this section focuses on rehabi- litation following injury, mostly stroke, one of the major sources of brain injuries. Hesse and Werner provide a broad review of all the rehabilitation approaches that have been used to promote recovery of motor function following stroke.
Nudo and his colleagues then focus on the neural bases for
new therapies for maximizing the recovery process. Bruce
Dobkin discusses the challenges that remain ahead of us to
link plasticity processes at various levels of analysis to recov-
ery of motor function after stroke. This theme is further devel-
oped in the following chapter by Winstein and Prettyman
who focus on constraint-induced (CI) therapy for functional recovery after stroke. After discussing the detailed principles underlying this therapy, they review the potential biological mechanisms that could account for the effects of CI therapy.
Finally, Cynthia Thompson reviews neuroimaging studies applied to understand recovery of language functions in aphasic patients with left or right hemispheric lesions. The third part of this section covers various approaches using stem cell grafting coupled with different gene technologies that are being explored to repair CNS damage. Whittemore and colleagues review numerous studies using a variety of stem cells to repair spinal cord injury, and they stress the fact that we need to better understand the factors involved in the differentiation of these cells in various locations. This is followed by a chapter by Popovic, Petersen, and Brundin reviewing a large number of studies performed in rodents, nonhuman primates, and humans to use stem cell implants to treat Huntington’s disease. Although the authors are opti- mistic that a grafting approach will ultimately work, they do stress the need to obtain a better source of stem cells for implantation and better understanding of the factors needed for optimal survival of the grafted cells. The final chapter of this section by Do¨bro¨ssy and Dunnett further elaborates on this theme and discusses how interactions between external manipulations might provide optimal conditions for survival of grafted cells, thus linking the rehabilitation and the cell therapies together.
The last section of the book is devoted to the final line of
research discussed above, namely engineering approaches to
understand mechanisms of plasticity and develop new thera-
pies based on these principles. The group of Sam Deadwyler
reviews some of the recent work applying a variety of algo-
rithms to examine the reliability and dynamics of hippocam-
pal neural representations of information. They demonstrate
that the analysis of the activity of a relatively small group of
neurons is sufficient to provide an adequate prediction of the
animal’s behavior. David Krupa summarizes on-going work
in a number of laboratories directed at developing so-called
brain–machine interfaces (BMI) that would eventually be
used to restore lost brain functions. The need for further basic research before such devices can be successfully implanted in humans is stressed. Finally, the group of Ted Berger provides an update on their on-going work directed at developing implantable biomimetic devices that can replace damaged brain regions involved in cognitive func- tions. Their work represents the perfect illustration of the overall theme of the book, as it starts from the understand- ing of basic mechanisms of synaptic transmission and infor- mation processing, processes through the development of VLSI devices reproducing the functions of large groups of neurons, and ends at the clinical level to improve the condi- tions of large numbers of patients suffering loss of cognitive abilities.
Overall, we wish to thank each of the contributors who have provided what we believe will be extremely useful infor- mation for a wide range of neuroscientists and clinicians interested in understanding the basic mechanisms of CNS plasticity and the potential clinical applications of these mechanisms to recover functions that are lost as a result of disease or injury.
Michel Baudry
Xiaoning Bi
Steven S. Schreiber
Preface . . . . iii Contributors . . . . xvii
1. Memory: From Molecular Mechanisms to Clinical
Applications . . . . 1 Michel Baudry
1. Introduction . . . . 1
2. LTP: A Cellular Mechanism for Learning and Memory . . . . 2
3. Current Hypotheses for LTP=LTD Mechanisms . . . . 9 4. Ampakines, LTP, and Memory . . . . 13
5. Clinical Trials of Ampakines . . . . 15 6. Conclusions . . . . 16
References . . . . 16
2. Synaptogenesis as a Correlate of Activity-Induced
Plasticity . . . . 25 Irina Nikonenko, Pascal Jourdain, Bemadett Boda, and
Dominique Muller
1. Introduction . . . . 25
2. Changes in Spine Dynamics with Activity . . . . 26 3. Modulation of Spine Morphology by Activity . . . . 26 4. Evidence for Activity-Induced Synaptogenesis . . . . 28 5. Postsynaptic Mechanisms Controlling Activity-Induced
Synaptogenesis . . . . 30
6. Activity-Induced Remodeling of Presynaptic Terminals . . . . 31
ix
7. Conclusions . . . . 32 References . . . . 33
3. Volume Transmission: Role in the Carry-Over Functional
Effect in Tactile Vestibular Substitution? . . . . 39 Paul Bach-y-Rita
1. Volume Transmission . . . . 39
2. The History of Volume Transmission . . . . 42 3. Computational Neuroscience VT Studies . . . . 44 4. Carry-Over Functional Effect in Tactile Vestibular
Substitution? . . . . 47 References . . . . 48
4. Lysosomal Dysfunction in Brain Aging and Neurodegeneration:
Roles in Trophic Signaling and Neuroinflammation . . . . 53 Xiaoning Bi
1. Lysosomal Dysfunction and Brain Aging . . . . 53 2. Lysosomal Dysfunction and Trophic Endosomal
Signaling . . . . 57
3. Lysosomal Dysfunction and Neuroinflammation . . . . 58 4. Roles of Lysosomal Dysfunction in Brain Aging and
Neurodegeneration: A Hypothesis . . . . 62 References . . . . 64
5. Axonal Sprouting in the Adult Brain: Mechanisms of Lesion-Specific Sprouting of the Corticostriatal Pathway
in Adult Rats . . . . 75 Marie-Francoise Chesselet, S. Thomas Carmichael,
Marc Shomer, Dorothy Harris, and Veronique Riban 1. Introduction . . . . 75
2. Lesion-Specific Axonal Sprouting of the Corticostriatal Pathway . . . . 76
3. The Role of Electrophysiological Activity in Axonal Sprouting in the Adult Brain . . . . 80
4. Myelin-Associated Proteins and Axonal Sprouting in the Adult Brain . . . . 85
5. Conclusion . . . . 85
References . . . . 86
6. Behavioral Implications for the Activity Dependent
Regulation of Neurotrophins . . . . 89 Fernando Gomez-Pinilla and Shoshanna Vaynman
1. Introduction . . . . 89
2. Cell Biology of NTs . . . . 90
3. Neurotrophins and Neural Activity . . . . 95
4. Neurotrophins and Learning and Memory . . . . 101 5. Neurotrophins and Behavior and Lifestyle:
Experience-Dependent Plasticity . . . . 107 6. Conclusions and Research Demands . . . . 118
References . . . . 118
7. Estrogen Therapy for Prevention of Alzheimer’s Disease But Not for Rehabilitation Following Onset of Disease:
The Healthy Cell Bias of Estrogen Action . . . . 131 Roberta Diaz Brinton
1. Introduction . . . . 131
2. Alzheimer’s Disease: A Potential Health Crisis . . . . 132 3. Hormone Replacement Therapy (HRT) and Risk of
Developing AD: Importance of the Time of Onset and the Type of HRT . . . . 133
4. The Role of Estrogen in Cognitive Functions . . . . 140 5. How Might Estrogen-Replacement Therapy Reduce
the Risk of AD? . . . . 146
6. Speculations on When to Intervene with Estrogen-Replacement Therapy . . . . 149 7. Summary . . . . 151
References . . . . 152
8. The Use of PET to Evaluate Neural Plasticity and Repair in Rodent Brain . . . . 159 Harley I. Kornblum, Keith J. Tatsukawa,
S. Thomas Carmichael, and Simon R. Cherry 1. Introduction . . . . 159
2. Principles of PET . . . . 160
3. Dedicated Lab Animal PET Scanners . . . . 163 4. Studies of Glucose Utilization and
Neuroplasticity . . . . 164
5. Other Potential Applications of PET in Neuroplasticity . . . . 168
6. Current Limitations for the Use of PET in Studies of Rodent CNS Plasticity . . . . 169
7. Comparison of PET to Other In Vivo Functional Imaging Modalities . . . . 171
References . . . . 173
9. Use of Estrogens as Neuroprotectants in Stroke and
Alzheimer’s Disease . . . . 175 James W. Simpkins, Shao-Hua Yang, and Yi Wen
1. Introduction . . . . 175
2. Estrogen Physiology and Pharmacology . . . . 176 3. Current Clinical Uses of Estrogens . . . . 176
4. Evidence for Efficacy of Estrogens and Estrogen Analogs in Stroke Neuroprotection . . . . 177
5. Transient Cerebral Ischemia as a Model for Alzheimer’s Disease Neuropathology . . . . 180
6. Need for Further Studies . . . . 183 References . . . . 183
10. Cell Death After Spinal Cord Injury: Basic Mechanisms and Potential Therapeutic Approaches to Promote Functional
Recovery . . . . 189 Steven S. Schreiber
1. Apoptosis vs. Necrosis . . . . 190 2. Molecular and Cellular Mechanisms of
Apoptosis . . . . 191
3. Evidence for Apoptosis After SCI . . . . 195 4. Prevention of Apoptosis After SCI . . . . 198 5. Conclusion . . . . 200
References . . . . 200
11. Motor Rehabilitation After Stroke: Novel Physical
Treatment Strategies . . . . 209 Stefan Hesse and Cordula Werner
1. Introduction . . . . 209
2. General Principles of Physical Therapy . . . . 210
3. Special Aspects of Upper Limb Rehabilitation . . . . 210 4. Special Aspects of Gait Rehabilitation . . . . 218
5. Summary . . . . 224 References . . . . 224
12. Neural Bases for Rehabilitation After Stroke . . . . 229 Randolph J. Nudo, Ann M. Stowe, Ines Eisner-Janowicz, and Numa Dancause
1. Animal Models of Stroke and Rehabilitation . . . . 230 2. Effects of Motor Injury on Behavioral Function:
Recovery and Compensation . . . . 231 3. Neurophysiological Consequences of
Motor Cortex Injury . . . . 233
4. Influence of Postinjury Motor Experience on Reorganization of Motor Maps . . . . 238 5. Anatomical Consequences Following
Motor Cortex Injury . . . . 239
6. Influence of Postinjury Motor Experience on Neuroanatomical Plasticity . . . . 241
7. New Approaches to Maximize Neuroplasticity and Recovery After Stroke . . . . 243
8. Summary . . . . 245 References . . . . 245
13. Plasticity of Language Networks . . . . 255 Cynthia K. Thompson
1. Neuroimaging Studies . . . . 256
2. Factors Related to Neuroplastic Processes . . . . 260 3. Conclusion . . . . 267
References . . . . 267
14. Locomotor Training-Induced Plasticity . . . . 271 Bruce H. Dobkin
1. Introduction . . . . 271
2. The Distributed Locomotor System . . . . 271 3. Interventions to Drive Activity-Dependent
Plasticity . . . . 275
4. Summary . . . . 276 References . . . . 277
15. Constraint-Induced Therapy for Functional Recovery After Brain Injury: Unraveling the Key Ingredients
and Mechanisms . . . . 281 C. J. Winstein and M. G. Prettyman
1. Introduction . . . . 281
2. Essentials of Constraint-Induced Therapy: What is the Evidence? . . . . 284
3. Two Complementary Mechanisms Underlying CI Therapy:
What is the Evidence? . . . . 310 References . . . . 317
16. Stem Cell Grafting and Spinal Cord Injury . . . . 329 Richard L. Benton, Gaby U. Enzmann, and
Scott R. Whittemore
1. Introduction . . . . 329
2. Neural Stem Cell Transplantation in the Spinal Cord . . . . 330
3. Immortalized Cell Transplantation in the Spinal Cord . . . . 342
4. Bone Marrow and Stromal Stem Cell
Transplantation in the Spinal Cord . . . . 347 5. Conclusions . . . . 351
References . . . . 351
17. Stem Cells and Huntington’s Disease . . . . 361 N. Popovic, A ˚ . Peterse´n, J.-Y. Li, and P. Brundin
1. Features of Huntington’s Disease . . . . 361 2. Symptoms of HD . . . . 364
3. Strategies in the Treatment of HD . . . . 365 4. Striatal Neural Transplantation in
Nonhuman Primates . . . . 372
5. Clinical Transplantation Trials in HD . . . . 374
6. Risk Factors of Neural Transplantation . . . . 378
7. Neurogenesis in HD . . . . 378 8. Conclusion . . . . 379
References . . . . 381
18. Plasticity, Cell Transplantation, and Brain Repair . . . . 395 Maˇte´ D. Do¨bro¨ssy and Stephen B. Dunnett
1. Introduction . . . . 395
2. Cell Transplantation and Plasticity . . . . 396 3. Enhancing Graft Function . . . . 399
4. The Influence of Behavioral Experience and Training on Graft Function . . . . 404 5. The Choice of Cells . . . . 410
6. Conclusion: Plasticity and the Clinical Application of Cell Replacement Therapy . . . . 412
References . . . . 413
19. Brain-Implantable Biomimetic Electronics as Neural
Prostheses to Restore Lost Cognitive Function . . . . 423 Theodore W. Berger, Ashish Ahuja, Patrick Nasiatka, Spiros H. Courellis, Gopal Erinjippurath, Ghassan Gholmieh, John J. Granacki, Min Chi Hsaio, Jeffrey LaCoss, Vijayaraghavan Srinivasan, Vasilis Z. Marmarelis, Dong Song, Armand R.
Tanguay, Jr., and Jack Wills 1. Introduction . . . . 424
2. The System: Hippocampus . . . . 425
3. General Strategy and System Requirements . . . . 427 4. Proof-of-Concept: Replacement of the CA3 Region of the
Hippocampal Slice with a Biomimetic Device . . . . 429 5. Experimental Characterization of Nonlinear Properties
of the Hippocampal Trisynaptic Pathway . . . . 430 6. Nonlinear Dynamic Modeling of CA3 Input/Output
Properties . . . . 432
7. Microcircuitry Implementation of the CA3 Input/Output Model . . . . 439
8. Conformal, Multisite Electrode Array Interface . . . . 447 9. System Integration: Current Status of the Hippocampal
Slice Prosthetic . . . . 451
References . . . . 453
20. Behaviorally Relevant Neural Codes in Hippocampal
Ensembles: Detection on Single Trials . . . . 459 John D. Simeral, Robert E. Hampson, and Sam A. Deadwyler
1. Introduction . . . . 459
2. Recording and Analysis Methods . . . . 460 3. Representation of Phase and Position . . . . 465 4. Detection and Dynamics of Representations . . . . 471
References . . . . 473
21. Recent Advances Toward Development of Practical
Brain–Machine Interfaces . . . . 477 David J. Krupa
1. Brain–Machine Interfaces . . . . 477 2. Input BMIs . . . . 480
3. Output BMIs . . . . 484
4. Closed-Loop Input–Output BMIs . . . . 492 5. Conclusions . . . . 495
References . . . . 495
Index . . . . 503
Ashish Ahuja Department of Electrical Engineering and Center for Neural Engineering, University of Southern California, Los Angeles, California, U.S.A.
Paul Bach-y-Rita Departments of Orthopedics and Rehabilitation Medicine, and Biomedical Engineering, University of Wisconsin, Madison, Wisconsin, U.S.A.
Michel Baudry Department of Biology, Neuroscience Program, University of Southern California, Los Angeles, California, U.S.A.
Richard L. Benton Kentucky Spinal Cord Injury Research Center (KSCIRC), Department of Neurology, University of Louisville School of Medicine, Louisville, Kentucky, U.S.A.
Theodore W. Berger Department of Biomedical Engineering, Center for Neural Engineering, and Program in Neuroscience, University of Southern California, Los Angeles, California, U.S.A.
Xiaoning Bi Department of Psychiatry & Human Behavior, University of California, Irvine, Irvine, California, U.S.A.
Bemadett Boda Neuropharmacology, Centre Medical Universitaire, Geneva, Switzerland
Roberta Diaz Brinton Department of Molecular Pharmacology and Toxi- cology and Program in Neuroscience, Pharmaceutical Sciences Center, University of Southern California, Los Angeles, California, U.S.A.
xvii
P. Brundin Section for Neuronal Survival, Wallenberg Neuroscience Center, Department of Physiological Sciences, Lund University, Lund, Sweden
S. Thomas Carmichael Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.
Simon R. Cherry Department of Biomedical Engineering, University of California Davis, Davis, California, U.S.A.
Marie-Francoise Chesselet Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.
Spiros H. Courellis Department of Biomedical Engineering and Center for Neural Engineering, University of Southern California, Los Angeles, California, U.S.A.
Maˇte´ D. Do¨bro¨ssy The Brain Repair Group, Cardiff School of Biosciences, Cardiff University, Cardiff, Wales, U.K.
Numa Dancause Center on Aging and Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas, U.S.A.
Sam A. Deadwyler Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, U.S.A.
Bruce H. Dobkin Department of Neurology, Geffen School of Medicine, Neurologic Rehabilitation and Research Program, University of California Los Angeles, Los Angeles, California, U.S.A.
Stephen B. Dunnett The Brain Repair Group, Cardiff School of Biosciences, Cardiff University, Cardiff, Wales, U.K.
Ines Eisner-Janowicz Center on Aging and Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas, U.S.A.
Gaby U. Enzmann Kentucky Spinal Cord Injury Research Center (KSCIRC), Department of Neurology, University of Louisville School of Medicine, Louis- ville, Kentucky, U.S.A.
Gopal Erinjippurath Department of Biomedical Engineering, University of Southern California, Los Angeles, California, U.S.A.
Ghassan Gholmieh Department of Biomedical Engineering and Center for Neural Engineering, University of Southern California, Los Angeles, California, U.S.A.
Fernando Gomez-Pinilla Department of Physiological Science, University of California at Los Angeles, Los Angeles, California, U.S.A.
John J. Granacki Departments of Biomedical Engineering and Electrical Engineering, Center for Neural Engineering, and Information Sciences Institute, University of Southern California, Los Angeles, California, U.S.A.
Robert E. Hampson Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, U.S.A.
Dorothy Harris Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.
Stefan Hesse Klinik Berlin, Department of Neurological Rehabilitation, Free University Berlin, Berlin, Germany
Min Chi Hsaio Department of Biomedical Engineering and Center for Neural Engineering, University of Southern California, Los Angeles, California, U.S.A.
Pascal Jourdain Neuropharmacology, Centre Medical Universitaire, Geneva, Switzerland
Harley I. Kornblum Department of Pharmacology, University of California at Los Angeles, School of Medicine, Los Angeles, California, U.S.A.
David J. Krupa Department of Neurobiology, Duke University Medical Center, Durham, North Carolina, U.S.A.
Jeffrey LaCoss Information Sciences Institute, University of Southern California, Los Angeles, California, U.S.A.
J.-Y. Li Section for Neuronal Survival, Wallenberg Neuroscience Center, Department of Physiological Sciences, Lund University, Lund, Sweden Vasilis Z. Marmarelis Departments of Biomedical Engineering and Electrical Engineering, and Center for Neural Engineering, University of Southern California, Los Angeles, California, U.S.A.
Dominique Muller Neuropharmacology, Centre Medical Universitaire, Geneva, Switzerland
Patrick Nasiatka Department of Electrical Engineering and Center for Neural Engineering, University of Southern California, Los Angeles, California, U.S.A.
Irina Nikonenko Neuropharmacology, Centre Medical Universitaire, Geneva, Switzerland
Randolph J. Nudo Center on Aging and Department of Molecular and Inte- grative Physiology, University of Kansas Medical Center, Kansas City, Kansas, U.S.A.
A˚ . Peterse´n Section for Neuronal Survival, Wallenberg Neuroscience Center, Department of Physiological Sciences, Lund University, Lund, Sweden N. Popovic Section for Neuronal Survival, Wallenberg Neuroscience Center, Department of Physiological Sciences, Lund University, Lund, Sweden M. G. Prettyman Department of Biokinescology Physical Therapy, Univer- sity of Southern California, Los Angeles, California, U.S.A.
Veronique Riban Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.
Steven S. Schreiber Department of Neurology, and Anatomy and Neuro- biology, UCI College of Medicine, Irvine; and Neurology Section, VA Long Beach Healthcare System, Long Beach, California, U.S.A.
Marc Shomer Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.
John D. Simeral Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, U.S.A.
James W. Simpkins Department of Pharmacology and Neuroscience, Uni- versity of North Texas Health Science Center, Fort Worth, Texas, U.S.A.
Dong Song Department of Biomedical Engineering and Center for Neural Engineering, University of Southern California, Los Angeles, California, U.S.A.
Vijayaraghavan Srinivasan Information Sciences Institute, University of Southern California, Los Angeles, California, U.S.A.
Ann M. Stowe Center on Aging and Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas, U.S.A.
Armand R. Tanguay, Jr. Departments of Electrical Engineering, Biomedi- cal Engineering, and Materials Science; Center for Neural Engineering; and Program in Neuroscience, University of Southern California, Los Angeles, California, U.S.A.
Keith J. Tatsukawa Department of Pediatrics, University of California at Los Angeles, School of Medicine, Los Angeles, California, U.S.A.
Cynthia K. Thompson Department of Communication Sciences and Dis- orders, and Neurology, Cognitive Neurology and Alzheimer’s Disease Center, Northwestern University, Evanston, Illinois, U.S.A.
Shoshanna Vaynman Department of Physiological Science, University of California at Los Angeles, Los Angeles, California, U.S.A.
Yi Wen Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas, U.S.A.
Cordula Werner Klinik Berlin, Department of Neurological Rehabilitation, Free University Berlin, Berlin, Germany
Scott R. Whittemore Kentucky Spinal Cord Injury Research Center (KSCIRC), Department of Neurology, University of Louisville School of Medicine, Louisville, Kentucky, U.S.A.
Jack Wills Department of Electrical Engineering and Information Sciences Institute, University of Southern California, Los Angeles, California, U.S.A.
C. J. Winstein Department of Biokinescology Physical Therapy, Univer- sity of Southern California, Los Angeles, California, U.S.A.
Shao-Hua Yang Department of Pharmacology and Neuroscience, Univer- sity of North Texas Health Science Center, Fort Worth, Texas, U.S.A.
1
Memory: From Molecular Mechanisms to Clinical Applications
Michel Baudry
Department of Biology, Neuroscience Program, University of Southern California, Los Angeles, California, U.S.A.
1. INTRODUCTION
Memory is a phenomenon that has fascinated scientists as well as writers, philosophers, and common people since the beginning of mankind. As has been repeatedly underlined, memory is both incredibly powerful and fragile;
we all have memories that date back to our infancy, and at the same time, we can forget what we did yesterday or where we parked our car this morn- ing. For the biologist, memory is a remarkable feature of the nervous system, and its unique properties have attracted the interest of scientists from every field, ranging from molecular biologists to psychologists and even to physicists and mathematicians. Ever since the identification of the synaptic contacts as the sites of communication between neurons, the preva- lent notion for the cellular mechanisms underlying the storage of informa- tion in the CNS has been some form of activity-dependent modification of synaptic efficacy. This idea, already present in Ramon y Cajal’s writing, was further popularized by Hebb (1), and, many years after Hebb’s death led to the now famous concept of hebbian synapse (2,3). Unfortunately, the search for the cellular mechanisms of memory got a bad reputation fol- lowing a series of experiments attempting to demonstrate that, while the genes held the memories of the species, proteins were the repositories for the memories of the individuals. These attempts resulted in the infamous
1
transfer of memory experiments, in which extracts from trained worms were fed to naive worms or brain extracts from trained mice were injected into naive mice (4–7). While experimental psychologists were making great pro- gress at providing a classification of various forms of memory (8), the search for the cellular mechanisms remained limited to the study of some simple systems such as the sensitization of the gill withdrawal reflex in Aplysia (9) or the acquisition of classical conditioning in Hermissenda (10). How- ever, an important discovery, published in 1973, forever changed our views of the cellular mechanisms of learning and memory (11). After failing to find synaptic plasticity in neocortex as a Ph.D. student, Bliss (12) moved to Per Andersen’s laboratory. There, Bliss and Lomo discovered a form of activity- dependent modification of synaptic plasticity at hippocampal synapses that exhibited several features expected of a cellular mechanism of learning and memory. They called it long-lasting potentiation, but it soon became known and referred to as long-term potentiation or LTP. Over the last 30 years, this phenomenon has become the epicenter of the discussions related to the mechanisms of learning and memory, and, as we will discuss below, has gen- erated a wealth of information regarding not only the basic mechanisms of learning and memory but also the first rationale design of new molecules directed at improving learning disabilities resulting from diseases or old age. In this chapter, we will first review the features of LTP, and discuss why these features are well suited for a learning mechanism. We will then summarize the current hypotheses that have been proposed to explain LTP, and to account for the links between LTP and learning and memory (Fig. 1). This will be followed by a review of the properties of positive AMPA receptor modulators, the ampakines, and of the studies indicating that they facilitate LTP formation and improve learning in a variety of tasks. The review will conclude by a brief survey of the various clinical trials currently evaluating these molecules for selected indications.
2. LTP: A CELLULAR MECHANISM FOR LEARNING AND MEMORY
As often the case in experimental sciences, LTP was discovered by serendip- ity when Bliss and Lomo were trying to study the characteristics of the per- forant path input to the dentate gyrus in anesthetized rabbits (see Ref. 13).
In order to maintain the size of the evoked responses, they noticed that when they delivered brief episodes of high frequency stimulation, evoked responses would get bigger and remained bigger for long periods of time.
Thus, the expression ‘‘long lasting potentiation’’ was created; when similar experiments were performed in acute hippocampal slices and resulted in a similar long-lasting enhancement of excitatory synaptic transmission (14–16), the expression long-term potentiation (LTP) took over, and, with
a few exceptions, is now universally used to design a long-lasting increase in monosynaptic transmission resulting from a brief train of high frequency stimulation, typically 100 Hz.
2.1. Features of LTP
As already mentioned, three of the initial features of the LTP phenomenon were immediately stressed as potential links with memory processes; rapid induction, long duration and prominent expression in the hippocampus, a structure that the work of Scoville and Milner (17) had previously demonstrated to be critical in memory formation. Shortly after came the demonstration that LTP exhibited some forms of associativity that could Figure 1 Links between LTP, learning and memory, and cellular processes. The relationships between LTP and learning and memory have been generally explored with three complementary approaches. The features of various forms of LTP have been compared with those of various forms of learning and memory. Pharmacologi- cal tools derived from the molecular=cellular studies of LTP have been applied on various forms of learning and memory. Finally, targeted mutations of specific genes identified from molecular studies of LTP have been tested for their effects on various forms of learning and memory.
account for some of the associative properties of learning and memory (2,18), although this point has recently been challenged (19). It was also initially recognized that LTP was prominently expressed at excitatory synapses using glutamate as a neurotransmitter. The existence of an LTP-like phenomenon at synapses using a different neurotransmitter such as GABA has been diffi- cult to demonstrate convincingly until now (see Refs. 20–22). For years, an intense debate opposed the supporters of a presynaptic hypothesis for the site of expression of LTP to those of the postsynaptic localization of the changes in synaptic transmission underlying LTP (see Refs. 23–25). For the former, increased glutamate release or increase in the probability of release was the likely explanation for increased transmission (26). For the later, increased number of glutamate receptors or increased currents gated by glutamate receptors were more likely to account for the characteristics of LTP. Based on a number of studies directed at understanding the regulation of the proper- ties of glutamate receptors, we proposed in 1984 that LTP was due to changes in glutamate receptors triggered by the activation of a calcium-dependent protease, calpain (27). In our model, we also discussed the possibility that cal- pain activation resulted in modifications of the structures of the dendritic spines, making them more stable and providing for the long duration of LTP. As we will discuss later, this idea is still one of the most widely accepted idea for the cellular mechanisms responsible for the increased synaptic trans- mission in LTP. At the time we proposed our LTP model, little was known regarding the characteristics of the glutamate receptors. Dramatic progress were made in the mid-1980s following the discovery that glutamate receptors could be subdivided into three classes of receptors, the N-methyl-d-aspartic acid (NMDA) receptors, the a-amino-3-hydroxy-5-methylisoxazole-4-pro- pionic acid (AMPA) receptors and the kainate receptors (28,29), and that a specific antagonist of the NMDA receptors, 2-amino-phosphonovalerate (APV) did not affect basal synaptic transmission but completely prevented LTP induction in CAl (30). This apparently paradoxical result was beauti- fully explained by Mayer et al. (31) and Nowack et al. (32), who indepen- dently found that magnesium blocked NMDA receptor channels in a voltage-dependent manner. When it was later on found that NMDA receptor channels were also calcium channels (33,34), most of the elements responsible for LTP induction were understood. These successive discoveries provided a general scheme for LTP formation, which is still currently valid (Fig. 2). As it was thus clear that an initial influx of calcium triggered by activation of NMDA receptors was necessary and sufficient to generate LTP (35–38), a myriad of calcium-dependent processes and enzymes have been proposed to play some role in LTP formation. The exact roles played by these different processes are still debated and will be discussed in later sections. In any event, this framework provided a rich field for pharmacologists and molecular biol- ogists to use their tools to attempt at dissecting out the roles of these processes in LTP, and thereby in learning and memory.
2.2. Pharmacology of LTP
As mentioned above, a very large number of biochemical events have been proposed to participate in one way or another in LTP induction or expres- sion over the last 20 years (39). Among these, several calcium-dependent processes have been identified (Fig. 3). Activation of the calcium-dependent protease, calpain, results in modifications of the structure of several cytoske- letal proteins and cell adhesion molecules and therefore is ideally suited to Figure 2 Schematic representation of the elements necessary and sufficient to induce LTP. It is now generally agreed that activation of NMDA receptors and the resulting increase in intracellular calcium are the necessary and sufficient events to induce LTP. The number of AMPA receptors present at the surface of dendritic spines is regulated by both a constitutive insertion of receptors and a regulated inser- tion, which could be the target of increased calcium concentration.
promote modifications in the structure of synaptic contacts (40). Activation of several protein kinases, and in particular, calcium=calmodulin kinase type II (CamKII), is also a key process to phosphorylate numerous proteins in synaptic contacts, including glutamate receptors (Table 1) (41). Autopho- sphorylation of CamKII might also provide for a form of short-term plasticity that exceeds the duration of the LTP-inducing stimulus (42,43).
Finally, activation of phospholipases provides for both the synthesis of lipid breakdown products with various signaling properties as well as for the breakdown of membrane lipids, an essential element for structural modifica- tions (44). It is interesting to point out that most of these cell biological processes are not unique to neurons but are present in many cell types where they participate in regulation of structure and function.
2.3. Genetic Manipulations of LTP
A much-debated issue in the LTP literature concerns the role of gene expres- sion and protein synthesis and the mechanisms linking LTP induction to the Figure 3 Various calcium-dependent processes triggered during LTP induction.
Several calcium-dependent enzymes and their main substrates have been proposed to participate in LTP.
protein synthesis machinery of neurons. Numerous studies have attempted to identify genes activated as a result of LTP induction (45–47). In most cases, several transcription factors are induced as a result of trains of elec- trical activity producing LTP. However, it has been quite difficult to further establish the relationship between gene induction with mechanisms underly- ing LTP expression and maintenance.
Advances in molecular biology techniques, and in particular, the possibility of knocking out or knocking in specific genes have produced a large number of mutant mice with various ‘‘learning and memory’’ im- pairments, in addition to problems with LTP induction or maintenance (Table 2) (48,49). In addition, the mutations that have been generated often affect enzymes, receptor=channels, or other cellular elements, which partici- pate in ‘‘normal’’ cellular functions, and are likely to modify even in a subtle way, various aspects of brain structure and function. The limitation on the role of gene expression in synaptic plasticity resulting from the cell-wide modifications it generally produces would be seriously eliminated if there were mechanisms coupling gene expression and local translation of the cor- responding mRNAs. For local protein synthesis to take place requires the dendritic targeting of mRNA and there are now a number of examples of such mRNAs (50–52). Furthermore, there is also experimental evidence for links between synaptic transmission and regulation of local protein synthesis as activation of glutamate metabotropic receptors in synapto- neurosomes has been shown to rapidly stimulate protein synthesis (53).
There are therefore two types of mechanisms by which synaptic activity can produce localized modifications of synaptic properties restricted to acti- vated synapses. In the first one, a small population of mRNAs is constitu- tively present in dendrites, and in response to an appropriate signal, these mRNAs are locally translated, and the newly synthesized proteins are incor- porated into the activated synapses. Note that this process is rapid and does not require gene expression, as it only depends on constitutively present mRNAs. In the second one, some locally generated signals are transmitted to the cell nucleus, trigger gene transcription, and the synthesis of mRNAs.
Table 1 a-CamKII and Synaptic Plasticity a-CamKII inhibitors block LTP induction in CA1
a-CamKII ko have impaired LTP and LTD in hippocampus and neocortex a-CamKII ko are severely impaired in Morris water maze; no problem to learn
visible platform
a-CamKII ko exhibit abnormal plasticity in visual cortex and somatosensory cortex Single-site mutation (Thr286!Ala) impairs LTP and spatial learning
Active a-CamKII ki also disrupts LTP and learning
See Ref. 43 for a recent review of the molecular basis for a role CamKII in LTP and learning and memory.
These mRNAs are targeted to the dendrites and locally translated at the appropriate site. Note that this requires the existence of a signal or signals that remain present at activated synapses for quite some time as the tran- scription of genes, and their targeting to the dendrites necessitate a signifi- cant period of time. This mechanism is somewhat related to the synaptic tagging described by Frey and Morris (54). In their model, these authors propose that LTP induction is accompanied by the activation of signals they call ‘‘synaptic tags,’’ which interact with plasticity-related newly synthesized proteins and stabilize the formation of LTP. Clearly, much more work is needed to clarify the exact mechanisms involved in this type of regulation, and to determine the types of mRNAs present in the dendrites, the mechan- isms involved in targeting them to dendrites and the signals responsible for tagging activated synapses. Finally, the types of proteins involved and their roles in regulating synaptic structure and function need to be further investigated.
2.4. Is LTP a Cellular Mechanism for Learning and Memory?
Long-term potentiation is the most widely proposed mechanism of memory storage in the hippocampus and neocortex. Although this issue is still debated, evidence supporting this hypothesis comes from a variety of Table 2 Effects of Gene Manipulation on Plasticity and Learning and Memory Gene modification Effect on synaptic plasticity Effect on learning
a-CamKII Impaired Impaired learning
Fyn Impaired Impaired learning
PKCg Impaired Impaired learning
MGluRl Impaired Impaired learning
PKA Normal Normal learning
GAP-43 overexpression Increased LTP Increased learning t-PA ko Decreased hippocampal LTP Impaired learning
Decreased striatal LTD
t-PA overexpression Increased LTP Increased learning BDNF overexpression Decreased CA1 LTP Impaired learning
BDNF ko Decreased LTP Normal learning
HD mutation Cognitive impairment
NR2b overexpression Increased plasticity Increased learning
Bcl-2 overexpression Increased learning
Human APP mutation Decreased LTP Decreased learning
HO-1 overexpression Impaired learning
Kvl.l antisense Treatment No effect on LTP Decreased learning Nociceptin receptor ko Impaired LTP Impaired learning
N-CAM ko Impaired LTP Impaired learning
experimental data and theoretical models (23,55–63). Long-term potentia- tion is prevalent in hippocampal and cortical networks and exhibits many properties required for a large capacity information storage device: rapid induction, associativity, long duration, and links with brain rhythms [in particular, the theta rhythm (64)]. Pharmacological manipulations or gene mutations interfering with LTP also interfere with various forms of learn- ing and memory, while pharmacological agents facilitating LTP formation also facilitate learning (Table 3). Finally, incorporating LTP-based rules in biologically realistic neuronal networks produces large capacity storage devices (65).
3. CURRENT HYPOTHESES FOR LTP=LTD MECHANISMS 3.1. Induction
The cellular events that are necessary and sufficient to produce LTP are now well understood (57,66). What is required is sufficient postsynaptic depolar- ization (ergo the high frequency bursts of stimulation) to relieve the NMDA receptor=channel from a voltage-dependent magnesium blockade and to produce a postsynaptic influx of calcium at the right place and of the right amplitude. The NMDA receptor thus functions as an AND gate (presynap- tic release of neurotransmitter and postsynaptic depolarization) and accounts for most features of LTP, such as associativity, calcium depen- dency, regulation by the degree of inhibition, etc. . . . It should be noted, however, that some forms of LTP do not require NMDA receptor activation, and thus there may be multiple forms of LTP as well as multiple ways of triggering the biochemical cascades leading to LTP (67).
3.2. Maintenance
It was clear from the outset that LTP could be due to changes in either the release characteristics of the presynaptic terminals or the postsynaptic responsiveness to the neurotransmitter or some combination of both factors. As some reports suggested that glutamate release was enhanced following LTP induction (68), the postsynaptic localization of NMDA Table 3 Pharmacology of LTP and of Hippocampal-Dependent Learning
Drug Target LTP Learning
AP-5 NMDAr Blockade Impairment
Ampakines AMPAr Facilitation Facilitation
Benzodiazepines GABAr Impaiment Impairment
Leupeptin Calpain Blockade Impairment
Protein synthesis inhibitors ? Blockade Blockade
receptors imposed the existence of some retrograde signals that could link LTP induction to LTP expression mechanisms. Several such signals were proposed such as arachidonic acid, nitric oxide (NO), or carbon monoxide (CO) (69). On the other hand, many reports have also indicated several post- synaptic modifications including changes in the properties of another type of glutamate receptors, the a-amino-3-hydroxy-5-methylisoxazole propionic acid (AMPA) receptors, and in the morphology and number of dendritic spines (70–72). There is now some general agreement that LTP expression is due to several modifications of the distribution of AMPA receptors and the structure of synaptic contacts (57).
3.2.1. Presynaptic Mechanisms
An increase in transmitter release obviously could account for an increase in synaptic transmission; it is generally admitted, for instance, that short-term potentiation is due to increased transmitter release (73). Biochemical and electrophysiological evidence has been obtained in support of the hypothesis that increased transmitter release accounts for LTP (68). Glutamate is the neurotransmitter used by synapses exhibiting LTP in various hippocampal pathways, and increased glutamate levels have been found after LTP induc- tion in perfusates obtained with push–pull cannulas implanted in the dentate gyrus (74). Increased glutamate release was also found after LTP induction in hippocampal slices and in synaptosomes prepared from hippocampus of rats in which LTP had been induced. Since the induction of LTP involves the postsynaptic activation of NMDA receptors, a retrograde signal has been postulated that relays the postsynaptic activation to the presynaptic terminal. Arachidonic acid was initially proposed to be such a retrograde signal since activation of NMDA receptors stimulates phospholipase A2
(PLA2), and PLA2inhibitors prevent LTP formation (75). Arachidonic acid could also provide a link with the presynaptic machinery involved in the reg- ulation of transmitter release because it activates protein kinases that have been shown to participate in phosphorylation reactions important for trans- mitter release. Nitric oxide as well as carbon monoxide were later proposed to be retrograde signals although the evidence for this conclusion remains highly controversial (57,76). While this mechanism could conceivably provide a satisfactory explanation for a short-lasting enhancement of transmitter release, in its present version it does not account for a long- lasting increase.
3.2.2. Quantal Analysis
Quantal analysis of synaptic transmission (77) is an approach that, in principle, could provide an unambiguous answer to the question of the locus of the changes underlying LTP. It uses the intrinsic variability of transmitter release and statistical methods to determine the parameters generally thought to govern synaptic transmission, i.e., the probability of
release, the number of release sites, and the elementary size of a postsynaptic response elicited by a quantum of neurotransmitter. Several groups have reported results obtained with quantal analysis in field CA1before and after LTP induction in hippocampal slices. Two groups observed an increase in quantal content (78,79), whereas one group observed an increase in quantal size (80), and another one both (81). In addition to this ambiguity in the results, quantal analysis requires a number of assumptions that might not be satisfied at hippocampal synapses. In particular, several studies have indi- cated the existence of synapses with functional NMDA receptors but few, if any, functional AMPA receptors (the so-called silent synapses) (82,83).
Transformation of silent synapses into active synapses by LTP-inducing stimulation could account for the inconsistencies in results from quantal analysis (57).
Finally, increased transmitter release could be accounted for by an increase in the number of synapses. Anatomical studies using quantitative electron microscopy have provided evidence that the number of certain categories of synapses, in particular sessile synapses, is increased in field CA1 following LTP induction (71,72). Although an increased number of synapses could explain the duration of LTP and account for its maintenance, it is not yet clear whether the increase in sessile synapses represents the for- mation of new synapses or the transformation of existing synapses by shape modifications (84,85) (see Nikonenko et al., this volume not available).
3.2.3. Changes in Spine Electrical Properties
Since their discovery, there has been much speculation concerning the roles of dendritic spines in synaptic transmission and the possibilities that synap- tic plasticity could be due to alterations in their electrical properties (86,87).
Because of their shape—large heads relative to long, narrow necks—they are considered to be high-resistance elements coupling voltage changes at the synapses with voltage changes in dendritic shafts. Based upon calculation and computer simulation, it has been proposed that decreased neck resis- tance could account for increased synaptic responses (88), which could affect the AMPA receptors more specifically than the NMDA receptors (89). Such a decrease in spine resistance could be due to an increase in neck dimension, and anatomical evidence indicates that LTP is accompanied by an increase in spines with wider and shorter necks. The recent discoveries of active elements (channels or pumps) in dendritic spines provide alternative means of modifying their electrical properties (90), although there is no evidence that these elements are modified following LTP induction.
3.2.4. Changes in Receptor Properties
One of the most important characteristics of LTP is that it is expressed by an increase in the component of the synaptic response resulting from the activation of the AMPA receptors with little changes in the component
