Download Dr. Coyle`s NIH Biosketch

OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015)
BIOGRAPHICAL SKETCH
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NAME:
Joseph T. Coyle, MD
eRA COMMONS USER NAME (credential, e.g., agency login): JTCOYLE
POSITION TITLE: Eben S. Draper Professor of Psychiatry and Neuroscience, Harvard Medical School and
McLean Hospital
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing,
include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)
INSTITUTION AND LOCATION
DEGREE
(if
applicable)
Completion
Date
MM/YYYY
FIELD OF STUDY
College of the Holy Cross, Worcester, MA
A.B.
06/1965
Philosophy
The Johns Hopkins School of Medicine
M.D.
Medicine
Johns Hopkins Hospital-Phipps Clinic
Residency
06/1969
07/197306/1976
Board Certified in Psychiatry (ABPN)
Neurobiology – Woods Hole Marine Biology Lab
1980
Certificate
08/2001
Psychiatry
Psychiatry
Neurobiology
A. Personal Statement
I have a forty-year record of translational research on the neurobiology of neuropsychiatric disorders
with a particular emphasis on the role of glutamatergic neurotransmission. An overarching goal has been to
develop animal models of neuropsychiatric disorder to understand the neurobiology of the disorder in order to
identify targets for more effective treatments. Specifically, my laboratory was the first to propose excitotoxicity
as a mechanism responsible for the selective neuronal degeneration in Huntington’s disease. We identified
the nucleus basalis as the source of cholinergic innervation to the cortex and its selective degeneration in
Alzheimer’s disease (AD). Thus, we proposed that pharmacologically correcting the cholinergic deficits in AD
would reduce the cognitive symptoms and demonstrated that galanthamine, an acetycholinesterase inhibitor,
should be an effective treatment (later marketed as Razolyne). Based on abnormalities in glutamatergic
markers in the post-mortem brains from subjects with schizophrenia, we proposed that hypofunction of NMDA
receptors might contribute to the symptoms of schizophrenia, especially the negative and cognitive symptoms.
To mimic NMDA receptor hypofunction, we genetically silenced the serine racemase (SR) gene, which
synthesizes D-serine, the NMDA receptor co-agonist in the forebrain and showed that SR-/- male mice
reproduced the neurochemical, structural and cognitive pathology of schizophrenia. Importantly, treating adult
SR-/- mice with D-serine reverses much of this schizophrenic pathology. I have also had a deep commitment
to training in research, especially under-represented minorities, through the Society for Neuroscience Minority
Training Grant with which I was associated over 15 years since its initiation under my presidency.
1. Coyle JT, Schwarcz R. Lesion of striatal neurones with kainic acid provides a model for Huntington's
chorea. Nature. 1976 Sep 16;263(5574):244-6. (Cited > 1200 times)
2. Coyle JT, Price DL, DeLong MR. Alzheimer's disease: a disorder of cortical cholinergic innervation.
Science. 1983 Mar 11;219(4589):1184-90. (Cited > 3000 times)
3. Tsai G, Passani LA, Slusher BS, Carter R, Baer L, Kleinman JE, Coyle JT. Abnormal excitatory
neurotransmitter metabolism in schizophrenic brains. Arch Gen Psychiatry. 1995 Oct;52(10):829-36. (Cited >
400 times)
4. Basu AC, Tsai GE, Ma CL, Ehmsen JT, Mustafa AK, Han L, Jiang ZI, Benneyworth MA, Froimowitz MP,
Lange N, Snyder SH, Bergeron R, Coyle JT. Targeted disruption of serine racemase affects glutamatergic
neurotransmission and behavior. Mol Psychiatry. 2009 Jul;14(7):719-27. (Cited > 175 times).
B. Positions and Honors
Positions and Employment:
1969-70 Intern in Pediatrics, The Johns Hopkins Hospital
1970-73 Research Associate, Laboratory of Clinical Science, National Institute of Mental Health (Dr. Julius
Axelrod), Bethesda, Maryland
1973-76 Resident in Psychiatry, Johns Hopkins Hospital
1974-76 Assistant Professor of Pharmacology, The Johns Hopkins School of Medicine
1978-80 Associate Professor of Pharmacology and Psychiatry, The Johns Hopkins School of Medicine
1980-91 Professor of Neuroscience, Psychiatry and Pharmacology, The Johns Hopkins School of Medicine
1982-91 Director, Division of Child Psychiatry, Professor of Psychiatry, Neuroscience, Pharmacology and
Pediatrics, The Johns Hopkins School of Medicine
1985-91 Distinguished Service Professor of Child Psychiatry
1991-01 Chairman, Consolidated Department of Psychiatry, Harvard Medical School
1991Eben S. Draper Professor of Psychiatry and of Neuroscience, Harvard Medical School
Other Experience and Professional Memberships:
American Association for the Advancement of Science (Fellow; Council, 2001-4; Chair for the
Neuroscience Section, 2014)
Society for Neuroscience (past-president; 1991).
American College of Neuropsychopharmacology (past-president; 2001)
Institute of Medicine of the National Academy of Sciences (1990)
American Academy of Arts and Sciences (1992)
Honors:
1978
A.E. Bennett Award in Basic Science from the Society of Biological Psychiatry
1979
John Jacob Abel Award from ASPET
Sato International Memorial Award from the Japanese Pharmaceutical Society
1982
Daniel Efron Award from the American College of Neuropsychopharmacology
1985
Foundations' Fund Prize for Research in Psychiatry, American Psychiatric Association
1985
Javits Neuroscience Investigator Award, NINDS
1986
Alpha Omega Alpha Honor Society
1988
McKnight Scholar in Neuroscience Award
1991
The Gold Medal Award from the Society of Biological Psychiatry
1994
The Salmon Lecture at the New York Academy of Medicine
1997
Robert J. and Claire Pasarow Foundation Award for Neuropsychiatric Research
2001
Society for Neuroscience Special Achievement Award
2004
Lieber Award for Schizophrenia Resaerch, NARSAD
2005
Society for Neuroscience, Award for “Lifelong Dedication to Excellence and Diversity in
Neuroscience”
2013
Julius Axelrod Award for Neuropharmacologic Research, Society for Neuroscience
2015
Google Scholar: >66,000 citations; h-index : >120; i10-index 569.
C. Contributions to Science:
1. With an interest in the developmental aspects of psychiatry, I asked my post-doctoral mentor, Julius
Axelrod, PhD, if I could study the development of the catecholaminergic neurons in the rat brain since virtually
nothing had been published on neurotransmitter development in the CNS. These initial studies demonstrated
that the noradrenergic neurons first expressed their all pre-synaptic markers (tyrosine hydroxylase,
norepinephrine (NE) and NE transporter) by 15 days gestation, well before the formation of the telencephalon.
In the cortex of the newborn, aminergic terminals are disproportionately heavily represented. Subsequent
studies in my laboratory showed that the presynaptic markers for cortical GABAergic neurons exhibited a
primarily post-natal development, consistent with their time of generation in the ventricular germinal zone. As
evidence was just emerging of cortical atrophy and GABAergic deficits in schizophrenia, we exploited the
ability of methylazoxymethanol (MAM) to selectively kill mitotically active cells but spare post-mitotic cells. We
used MAM to delete GABAergic neurons generated in the last week of rat gestation while sparing the postmitotic catecholaminergic neurons. The fetal MAM treatment resulted in cortical hypoplasia, absolute reduction
in presynaptic GABAergic markers and relative catecholaminergic hyper-innervation of the cortex, consistent
with our hypothesis. Recently, the Grace laboratory has shown that the MAM lesion model has face validity for
schizophrenia.
1. Coyle JT, Henry D. Catecholamines in fetal and newborn rat brain. J Neurochem. 1973 Jul;21(1):61-7.
(Cited >875 times).
2. Coyle JT, Enna SJ. Neurochemical aspects of the ontogenesis of GABAnergic neurons in the rat brain.
Brain Res. 1976 Jul 23;111(1):119-33. (Cited > 375 times).
3. Coyle JT, Molliver ME. Major innervation of newborn rat cortex by monoaminergic neurons. Science. 1977
Apr 22;196(4288):444-7. (Cited > 140 times).
4. Johnston MV, Grzanna R, Coyle JT. Methylazoxymethanol treatment of fetal rats results in abnormally
dense noradrenergic innervation of neocortex. Science. 1979 Jan 26;203(4378):369-71. (Cited >180 times).
2. I became aware of the interesting findings of John Olney that systemic treatment of newborn rats with
glutamate caused degeneration of neurons in the hypothalamus and retina where it accumulated in high
concentrations. Japanese pharmacologists had identified conformationally restricted analogues of glutamate
that were very potent glutamate receptor agonists. We demonstrated that the injection of kainic acid into the rat
striatum reproduced the neuropathology of Huntington’s disease with degeneration of of striatal GABAergic
neurons with sparing axons passing through or terminating (dopaminergic) in the striatum. We recognized that
in situ injection of an excitotoxin (kainic acid, ibotenic acid, NMDA) would be a powerful method for making
perikaryal specific brain lesions. This method permitted us to show that the nucleus basalis of Meynert was the
source of cholinergic innervation to the cortex, leading to the identification of its degeneration in AD. The
excitotoxin lesion method was been adopted widely in neuroscience. Subsequent research in my laboratory
demonstrated that oxidative stress was an important mediator of the excitotoxin induced neuronal
degeneration. The current proposal on traumatic brain injury with Dr. Liebl is particularly interesting as it brings
together my interests in translational neuroscience, excitotoxicity, and the role of D-serine as an NMDA
receptor co-agonist.
1. Coyle JT., Schwarcz R. Lesion of striatal neurons with kainic acid provides a model for Huntington’s
Disease. Nature 1976 263: 244-246. (Cited>1000 times).
2. Johnston MV, McKinney M, Coyle JT. Evidence for a cholinergic projection to neocortex from neurons in
basal forebrain. Proc Natl Acad Sci U S A. 1979 Oct;76(10):5392-6. (Cited >400 times).
3. Murphy TH, Miyamoto M, Sastre A, Schnaar RL, Coyle JT. Glutamate toxicity in a neuronal cell line involves
inhibition of cystine transport leading to oxidative stress. Neuron. 1989 Jun;2(6):1547-58. (Cited >600 times).
4. Coyle JT, Puttfarcken P. Oxidative stress, glutamate, and neurodegenerative disorders. Science. 1993 Oct
29;262(5134):689-95. (Cited >2800 times).
3. In post-mortem studies, AD, a prototypical “cortical” dementia, was shown by Peter Davies to be associated
with a substantial but selective reduction in presynaptic cholinergic markers in cortex, and our excitotoxin
lesion studies of the rat nucleus basalis demonstrated it to be the source of the cortical cholinergic projection.
We showed that the lesion resulted in a working memory deficit that could be reversed by treatment with
acetylcholinesterase inhibitors, providing proof of principle for the primary clinical treatment for AD for the last
twenty years. When the gene for amyloid precursor protein was mapped to HAS 21, we developed a mouse
model for Down Syndrome, the trisomy 16 (TS16) mouse, which has synteny with the Down Syndrome (DS)
region of HSA 21, to study the impact of over-expression of genes in this region on the early onset of AD in
DS. We showed that the development of the basal forebrain cholinergic neurons was impaired in TS16, which
could be normalized by treatment with nerve growth factor.
1. Whitehouse PJ, Price DL, Struble RG, Clark AW, Coyle JT, Delong MR. Alzheimer's disease and senile
dementia: loss of neurons in the basal forebrain. Science. 1982 Mar 5;215(4537):1237-9. (Cited > 2500 times).
2. Sweeney JE, Bachman ES, Coyle JT. Effects of different doses of galanthamine, a long-acting
acetylcholinesterase inhibitor, on memory in mice. Psychopharmacology (Berl). 1990;102(2):191-200. (Cited >
65 times)
3. Coyle JT, Oster-Granite ML, Reeves RH, Gearhart JD. Down syndrome, Alzheimer's disease and the
trisomy 16 mouse. Trends Neurosci. 1988 Sep;11(9):390-4. (Cited > 70 times).
4. Corsi P, Coyle JT. Nerve growth factor corrects developmental impairments of basal forebrain cholinergic
neurons in the trisomy 16 mouse. Proc Natl Acad Sci U S A. 1991 Mar 1;88(5):1793-7. (Cited 25 times).
4. In the context of clinical reports that dissociative anesthetics cause a syndrome resembling schizophrenia,
we found evidence of reduced glutamate and elevated NMDA receptor antagonist in a post-mortem study of
the cortex and hippocampus in schizophrenia, leading us to propose that NMDA receptor hypofunction could
be the cause of symptoms of schizophrenia, especially the cognitive and negative symptoms. To test this
hypothesis, we treated chronic schizophrenic patients stabilized on antipsychotic drugs with D-cycloserine
(DCS), which is a partial agonist at the glycine modulatory site (GMS) on the NMDA receptor, and showed that
DCS reduced negative symptoms and cognitive impairment. Working with the biotech, Trophix, we developed
the first glycine transport (GlyT1) inhibitor, NFPS, and demonstrated that the GMS was not saturated and thus
a drug target for enhancing NMDA receptor function. To create a model NMDA receptor hypofunction, we
developed a mutant mouse in which the gene for serine racemase (SR) was silenced. SR synthesizes Dserine, the GMS agonist in forebrain. Male SR-/- mice exhibited NMDA receptor hypofunction in vivo, reduced
LTP, cognitive impairments, cortical atrophy and dendritic atrophy. Using cell specific conditional knockouts of
SR, we showed that SR and D-serine were localized to cortical pyramidal neurons and GABAergic interneurons but not astrocytes. Restoring D-serine levels in the adult SR-/- reversed the neurochemical,
neurophysiologic and cognitive deficits, suggesting that pharmacologic interventions to enhance NMDAR
function might actually reverse the neuropathology of schizophrenia and the core symptoms.
1. Goff DC, Coyle JT. The emerging role of glutamate in the pathophysiology and treatment of schizophrenia.
Am J Psychiatry. 2001 Sep;158(9):1367-77.2. (Cited > 500 times).
2. Goff DC, Tsai G, Manoach DS, Coyle JT. Dose-finding trial of D-cycloserine added to neuroleptics for
negative symptoms in schizophrenia. Am J Psychiatry. 1995 Aug; 152(8):1213-5. (Cited > 260 times).
3. Bergeron R, Meyer TM, Coyle JT, Greene RW. Modulation of N-methyl-D-aspartate receptor function by
glycine transport. Proc Natl Acad Sci U S A. 1998 Dec 22; 95(26):15730-4. (Cited > 250 times).
4.Balu DT, Li Y, Puhl MD, Benneyworth MA, Basu AC, Takagi S, Bolshakov VY, Coyle JT. Multiple risk
pathways for schizophrenia converge in serine racemase knockout mice, a mouse model of NMDA receptor
hypofunction. Proc Natl Acad Sci U S A. 2013 Jun 25;110(26):E2400-9. doi: 10.1073/pnas. (Cited 30 times).
http://www.ncbi.nlm.nih.gov/sites/myncbi/joseph.coyle.1/bibliography/42359104/public/?sort=date&dir
ection=ascending.
D. Research Support
Ongoing Research Support
*R01MH051290 (Coyle)
08/01/1994–11/30/2017
NIH/NIMH
Psychosis and Brain Glutamate
The major goal of this project is to characterize the role of glycine and D-serine in modulating the NMDA
receptor.
Role: Principal Investigator
R01MH107884-01 (Chung)
9/10/2015 - 5/31/2020
NIH/NIM
iPSC Derived Human Cortical Interneurons as a Developmental Model of Schizophrenia
The major goal of this project is to take inducible pluripotent stem cells derived from fibroblasts from patients
with chronic schizophrenia and matched healthy controls and differentiate them into parvalbumin positive
cortical GABAergic neurons and determine how the neurons from the two populations may differ.
Role: Co-investigator
Completed Research Support (within the last 3 years)
*R21DA035427 (Coyle)
05/15/2013–07/31/2015
NIH/NIDA
Drug Abuse, Schizophrenia, NMDA Receptor
The major goal of this project is to determine whether the very high prevalence of substance abuse among
individuals with schizophrenia is the result of shared risk genes.
Role: Principal Investigator
R21MH1044505 (Rudolph)
07/01/2014–06/30/2016
NIH/NIMH
Neurobiological Relevance of 9p24.1 CNVs for Bipolar Disorder and Schizophrenia
The major goal of this project is to analyze changes in gene expression and in schizophrenia- and bipolar
disorder-related behaviors in 9p24.1 duplication and deletion mice.
Role: Co-Investigator
R21MH105732 (Levy)
09/05/2014-08/31/2016
NIH/NIMH
Targeting a Genetic Mutation in Glycine Metabolism with D-Cycloserine
The goals of this study are to characterize the neurobiology of a triplication of the glycine decarboxylase gene
and to determine the efficacy of augmentation with d-cycloserine.
Role: Co-Investigator
Not applicable.