Table Of ContentMolecular Origins of Human Attention
Molecular Origins of
Human Attention
The Dopamine-Folate Connection
by
Richard C. Deth Ph.D.
N ortheastern U niversity
Springer Science+Business Media, LLC
Molecular Origins of Human Attention The Dopamine-Folate Connection
Deth, Richard C.
ISBN 978-1-4613-5026-2 ISBN 978-1-4615-0335-4 (eBook)
DOI 10.1007/978-1-4615-0335-4
Copyright © 2003 by Springer Science+Business Media New York
Originally published by Kluwer Academic Publishers in 2003
Softcover reprint ofthe hardcover lst edition 2003
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Table ofContents
FORWARD .ix
ACKNOWLEDGEMENTS xi
CHAPTER 1 THEGIFTOF ATTENTION 1
CHAPTER2 AMOLECULARBASISFORATTENTION 5
CHAPTER3 HOWDOPAMINERECEPTORS WORK 15
CHAPTER4 THEDOPAMINED4RECEPTOR. 23
CHAPTER5 D4RECEPTOR-MEDIATED SOLID-STATE
SIGNALING .37
CHAPTER6 INTERNEURONS,D4RECEPTORS AND
ATTENTION 53
CHAPTER7 ATTENTION-BASEDLEARNING 67
CHAPTER 8 AWARENESS, ATTENTIONANDTHE
DETECTIONOFNOVELTY 75
CHAPTER9 ATTENTION AND METABOLISM 93
CHAPTER 10 THEEFFECTOFDRUGS ONATTENTION.........!11
CHAPTER 11 ATTENTION-DEFICITHYPERACTIVITY
DISORDER 125
CHAPTER 12 SCHIZOPHRENIA 149
CHAPTER 13 AUTISM 175
CHAPTER 14 OTHERPSYCHIATRICDISORDERS 193
CHAPTER 15 AN EVOLUTIONARYPERSPECTIVE 207
CHAPTER 16 THEGIFTOF WISDOM 219
REFERENCES 221
FOREWORD
Ithas indeed been a strangetrip. Back in 1994 I was a cardiovascular
pharmacologist studying molecular mechanisms that cause blood vessels to
contract. I had reliable funding from the National Institutes ofHealth for this
line of research. I lectured pharmacy students on the treatment of
hypertension, heart failure and renal failure. My academic career path had
been a logical, straight-line journey. I was making progress in my chosen
field, thefield in whichIwas originallytrained. Where didIgo wrong?
Something novel caught my attention. There was a structural pattern
within the family of neurotransmitter receptors we were studying, but there
was this one exception. Therein lies the story. The exception turned into a
mystery about why nature made this particular dopamine receptor, the D4
receptor subtype, different from all the others. Pursuing the answer to that
mystery has taken me far offthe straight-line route into dark and previously
unexplored scientific realms. It may sound a bit melodramatic, but take it
from me, there were indeeda numberofdark moments.
Literally, one thing led to another and soon my lab found that we
were working amidst tantalizing clues about mental illnesses such as
schizophrenia and autism. Some ofthe clues were dusty lines ofbiochemical
investigationthat seemed clearand importantbutneverquite connectedto the
core theories held by prominent researchers in the field. As we investigated
the relationship between this unique dopamine receptor and the folic acid
pathway we found the missing connections. Slowly we began to understand
how problems in folate or methionine metabolism might impair the normal
role of dopamine in attention and lead to psychiatric problems including
ADHD.
With our novel perspective we gradually explored mechanisms that
control folate-dependent methylation events in neural tissues. In doing so we
uncovered additional connections to psychiatric conditions. A case in point
wasthediscoverythatinsulin-likegrowthfactor-I powerfully stimulatedthese
reactions, providing a connection to developmental disorders and a new
explanation for the age-dependent onset ofschizophrenia. The highly potent
and specific inhibitory effects of ethanol forged links to alcoholism.
Discovery of copper's critical role made a link to Alzheimer's disease.
Perhaps most dramatic was the remarkably potent toxicity ofthimerosal, the
ethylmercury releasing preservative found in vaccines, creating a clear but
sinisterconnectionto autism.
Impairedattention plays a significant role in each ofthese psychiatric
conditions and it is the molecular basis of attention and attention-related
learning that binds them together. In writing this book I have attempted to
synthesize and integrate research from a number ofareas in order to arrive,at
a reasonable and cohesive description of the mechanism of attention. Of
necessityitis a moleculardescription, but ourcapacity for attention originates
at the molecular level. Unique molecular features ofD4 dopamine receptors
found only in humans andotherprimates provide a conceptual framework for
attention-based learning. Using these novel perspectives it is possible to
appreciate howgeneticandenvironmental factors cause disorders ofattention.
It is my hope that these molecular perspectives might lead to more effective,
mechanism-basedtreatmentapproaches forthesedisorders.
I have tried to make these fascinating molecular events accessible to
as many readers as possible but, like every worthwhile mystery, it is a
somewhat complex story. In particular I hope that motivated parents who are
seeking answers can find some within these pages despite the somewhat
technical vocabulary.
The process of writing this book has itself led to new insights and
stimulated new laboratory work. Specifically, the recognition that pieces of
the autism and pervasive developmental disorders puzzle fit together within
the unifying theme ofimpaired DNA methylation was a direct outgrowth of
writing Chapter 13. In subsequent collaborative studies we found that insulin
like growth factor-I, dopamine and thimerosal all cause profound changes in
DNAmethylation.
I offer a disclaimer about my scientific limitations. My perspective is
biased by the particular research findings made in my lab and I view the
molecular mechanism ofattention from this perspective. Opinions expressed
herein are those ofthe author. The molecular framework I describe is meant
to be a provocative stimulus for further investigation and confirmation. My
personal expertise is based upon knowledge ofmolecular function rather than
clinical experience. This is actually a good thing, since it is molecular-level
information that holds the key to understanding most mental illnesses.
Fictional scenarios are used to illustrate several psychiatric conditions. They
are meant to emphasize that while the topic may be molecules, the true arena
isthe humancondition.
Finally, I urge you to consider wandering offthe straight path every
now and then. Investigate something you find novel and interesting. Trust
your attention-based instincts and explore. You never know what you might
find.
R.C.Deth
ACKNOWLEGEMENTS
I am deeply grateful to the many graduate students and post-doctoral fellows
whose dedicated work in our laboratory not only generated dataand gotthem
their degrees butalso blazed a trail ofdiscovery that I have been fortunate to
share. Martin Kramer, Alok Sharma and Peter Wick were the first to embark
down the murky path leading to the secrets of the dopamine D4 receptor,
starting in 1995.Marty explored its unusual bindingbehavior and made initial
connections with methionine metabolism. Peter worked out a reasonably
facile method for measuring the movement of folate-derived methyl groups
through the receptor. Alok used this method to outline the basic features of
the cycle of dopamine-stimulated phospholipid methylation, including its
pharmacological specificity and its regulation by external factors. Alok
provideda strongplatformupon whichothers wouldbuild.
Mostafa Waly deserves special recognition. He first earned his M.S.
degree from Alexandria University in Egypt and quickly established himself
as the resident expert in nutrition and biochemistry within our pharmacology
environment at Northeastern University. Mostafa's skill and energy in the
laboratory were responsible for key findings about the potent effects of
ethanol and the regulatory role of insulin-like growth factor-I. He also
demonstrated the toxic effects ofheavy metals and characterized the potent
toxicity of thimerosal. Among many other students making significant
contributions to the D4 receptor story were Sung Shim, DaPei Liu, Wenbo
Tan, Ren Zhao, Suchitra Chari, Micki Nagata, Yuen Chen, Fran Power
CharnitskyandJorgeBenzecry. TimurTurkdogmanwas brave enoughto take
on the task of developing a computer simulation of dopamine-stimulated
phospholipid methylation for his doctoral thesis in mathematics. He also
providedwiseadvice duringthewritingofthis manuscript.
Collaborations were a vital in allowing the molecular events of
attentioncome intofocus. Curtis DuRand, then atthe VA Hospital in Bedford
Massachusetts, supervised clinical studies showing that defective
phospholipid methylation was a feature ofschizophrenia. He also brought a
great deal of methionine-related literature to my attention and fostered an
optimistic outlook during early stages ofthe work. Martha Teeter, his wife
and x-ray crystallographer par excellence, mentored me in the molecular
modeling ofdopamine receptors and gave me an appreciation ofhow protein
structure dictates function. During her several years in my lab YaFang Liu
made key observations about how the D4 receptor interacts with other
proteins via its primate-specific repeat segments. Ruma Banerjee, at the
University of Nebraska, generously agreed to measure methionine synthase
activity, a non-trivial task, and helped to show its remarkable dependence on
PI3-kinase signaling. Sang Woon Choi and Joel Mason at the Tufts
University/USDA Human Nutrition Research Center used their newly
developed mass spectrometry assay to demonstrate changes in DNA
methylation associated with PI3-kinase interventions and thimerosal. Barbara
Malewicz and Malak Kotb carried out phospholipid NMR studies and
methionine adenosyltransferase assays respectively. Their generosity and
willingness to help is greatlyappreciated.
I want to extend heartfelt thanks to Mimi Breed and to those at
Kluwer who had enough interest (and bravery) to publish this book. Mimi
prodded me along through the too many months ittookto finish writing and I
needed every last email. The opportunity to assemble a scientific story in the
scopeallowed bya monograph is a privilegethatIdon'tunderestimate.
In my real life, outside of the office and the laboratory, my wife
Maddy has been the constant anchor, friend and realist that has nurtured me
and kept me ontrack. Had she not beenthere for me each ofthe past 34 years
there is absolutely no doubtthat Iwould have wandered too far offthe path in
some hair-brained career choice or enterprise. Together with our children
JessicaandJoshweareafamily blessed with the wisdom and guidance ofour
parents, ourgrandparents andforthatwe will remain eternallygrateful.
1
THE GIFT OF ATTENTION
Attention. From the very first moments ofour ex utero existence it's
what we want. Even more, it is what we absolutely need for survival. At the
beginning we have no attention to give and can only take from others. Early
behaviorappearsto becompletely instinctual. However, inthe ensuingweeks,
subtle changes occurthat signal a transition from this primitive instinct-based
existence to the signs of an aware infant. Parents eagerly await this
comforting evidence indicating that their newborn can direct hislher attention
to a particular voice or sound. It is an early confirmation that those special
human capabilities, which we take too much for granted, are safe and sound
within the next generation. At least for now the gift ofattention is alive and
well. But, as we shall see, thejourneyis farfrom over.
What is really going on when a baby shifts its gaze to attend the
source oftheir mother's voice? It clearly has more significance than a simple
turn of the head. Perhaps it's more akin to tuning a radio to a certain
frequency sothat specific information can now flow. More like a camera lens
zooming in on a discrete portion ofthe overall scene, elevating it to a higher
prioritythanthe unattended background information. Atleast for the moment,
this is the information that really counts; the information they are "paying
attention"to. Theword "paying" ofcourse impliesthecapabilityofgiving out
attention and the gift ofa baby's attention is one ofthose transcendent joys
which defines parenthood.
Learning is intimately associated with attention. Although we sense
ortake ina vastamount ofinformation, we essentially learn only that portion
to which we have paid attention. In this way attention serves as our
discriminator between passive and active experiences. It is a mechanism by
which we can selectively prioritize certain sensory information above others.
This abilityto beselectivenodoubt increases ourlearning efficiency.
Attention has a dynamic, time-dependent nature. When we first "shift
attention" to something fresh it marks the start ofan ongoing process which
either wanes to an inattentive state or is terminated by a new episode of
attention. There is a natural tendency for the intensity of our attention to
lessenwithina secondortwo, despiteourbesteffortsto fully maintain it. One
important determinant ofthe duration and intensity is the familiarity ofthe
object of our attention. Is it new, interesting or even startling? Or, is it
familiar, expectedor even dull? Clearly it is more difficultto sustain attention
in the latter case. Novelty is a critical factor in determining the quality and
intensity ofattention. Man's interest in and pursuit ofnovelty is one our most
defining characteristics.
