Joseph T Coyle | Harvard Medical School (original) (raw)

Papers by Joseph T Coyle

Psychiatry Research: Neuroimaging, 2005

The objective of the present study was to examine patterns of cortical activation underlying d-cy... more The objective of the present study was to examine patterns of cortical activation underlying d-cycloserine&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#x27;s therapeutic efficacy in schizophrenic patients using functional magnetic resonance imaging (fMRI). We measured frontal and temporal lobe activation following a word fluency task in 12 subjects meeting DSM-IV criteria for schizophrenia at baseline and after 8 weeks of supervised treatment, using a double-blind, placebo-controlled design.

Human Molecular Genetics, Nov 2, 2017

Recent studies describe distinct DNA methylomes among phenotypic subclasses of neurons in the hum... more Recent studies describe distinct DNA methylomes among phenotypic subclasses of neurons in the human brain, but variation in DNA methylation between common neuronal phenotypes distinguished by their function within distinct neural circuits remains an unexplored concept. Studies able to resolve epigenetic profiles at the level of microcircuits are needed to illuminate chromatin dynamics in the regulation of specific neuronal populations and circuits mediating normal and abnormal behaviors. The Illumina HumanMethylation450 BeadChip was used to assess genome-wide DNA methylation in stratum oriens GABAergic interneurons sampled by laser-microdissection from two discrete microcircuits along the trisynaptic pathway in postmortem human hippocampus from eight control, eight schizophrenia, and eight bipolar disorder subjects. Data were analysed using the minfi Bioconductor package in R software version 3.3.2. We identified 11 highly significant differentially methylated regions associated with a group of genes with high construct-validity, including multiple zinc finger of the cerebellum gene family members and WNT signaling factors. Genomic locations of differentially methylated regions were highly similar between diagnostic categories, with a greater number of differentially methylated individual cytosine residues between circuit locations in bipolar disorder cases than in schizophrenia or control (42, 7, and 7 differentially methylated positions, respectively). These findings identify distinct DNA methylomes among phenotypically similar populations of GABAergic interneurons functioning within separate hippocampal subfields. These data compliment recent studies describing diverse epigenotypes among separate neuronal subclasses, extending this concept to distinct epigenotypes within similar neuronal phenotypes from separate microcircuits within the human brain.

Molecular Psychiatry, Mar 21, 2017

Proceedings of the National Academy of Sciences of the United States of America, May 24, 2004

N-methyl-D-aspartate receptor (NMDAR) activation requires both the binding of glutamate to its re... more N-methyl-D-aspartate receptor (NMDAR) activation requires both the binding of glutamate to its recognition site and occupancy of the strychnine insensitive glycine modulatory site (GMS). Pharmacological studies suggest that the glycine transporter, GlyT1, maintains subsaturating concentrations of glycine at synaptic NMDARs. To characterize further the role of GlyT1, we generated mice in which the gene encoding GlyT1 was inactivated by homologous recombination through insertion of a PGK-Neo cassette in place of exons 2 and 3. Real-time quantitative PCR revealed no transcripts in newborn homozygous [GlyT1(؊͞؊)] mice and a 50% reduction in heterozygous (HZ) [GlyT1(؉͞؊)] mice as compared with WT littermates. The activity of Na ؉-dependent glycine transport in forebrain homogenates was similarly affected. Homozygous mice died within 12 h of birth. In acute hippocampal slices, exogenous glycine or D-serine (10 M) enhanced NMDAR currents with Schaffer collateral stimulation in WT mice but not HZ mice, suggesting that the GMS was more occupied in the latter. The NMDAR͞␣amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor ratio of the excitatory postsynaptic currents was significantly increased in the HZ mice. In the water maze, the HZ mice exhibited better spatial retention. Furthermore, HZ mice were less sensitive to an amphetamine disruption of prepulse inhibition than WT mice but were more sensitive to the effects of MK-801. Thus, reduced expression of GlyT1 enhances hippocampal NMDAR function and memory retention and protects against an amphetamine disruption of sensory gating, suggesting that drugs which inhibit GlyT1 might have both cognitive enhancing and antipsychotic effects. glutamate ͉ glial cell ͉ memory ͉ prepulse inhibition G lycine (1) and͞or D-serine (2) are obligatory coagonists at the N-methyl-D-aspartate receptor (NMDAR) by binding to the strychnine-insensitive site on the NR1 subunit of the NMDAR permitting the subsequent binding of glutamate (3). The affinity of glycine for this glycine modulatory site (GMS) ranges from 0.1 to 3 M depending on the NR2 subtype of the NMDAR (4). Because the concentration of glycine in the cerebrospinal fluid is 5-10 M, it has been assumed that the GMS is saturated. However, Smith et al. (5) cloned a glycine high-affinity Na ϩ-dependent transporter, GlyT1, which is expressed in brain with a distribution that mirrors NMDAR localization. With the development of potent and specific antagonists of GlyT1, the role of GlyT1 in maintaining subsaturating levels of glycine at the glutamatergic synapse was established. Thus, in the acute hippocampal slice preparation, Bergeron et al. (6) demonstrated a robust enhancement of NMDAR responses of CA1 pyramidal cell to Schaffer collateral stimulation in the presence of the potent GlyT1 antagonist N-[3-(4Ј-f luorophenyl)-3-(4Ј-phenylphenoxy)] propylsarosine (NFPS). These findings have been replicated in a rat prefrontal cortex acute slice preparation (7). Together, these findings suggest that GlyT1 maintains subsaturating concentrations of glycine at the GMS on synaptic NMDARs. Kinney et al. (8) have reported that systemic administration of NFPS increases longterm potentiation in the dentate gyrus and enhances prepulse inhibition of acoustic startle (PPI), suggesting that inhibition of GlyT1 affects NMDAR function in a behaviorally relevant fashion. Although these findings with the relatively selective NFPS provide evidence of a functional role for GlyT1 in NMDAR function, we decided to examine further the effects of persistent hypofunction of GlyT1 by creating mice in which the gene encoding GlyT1 was inactivated by homologous recombination to ensure that these effects were indeed mediated by GlyT1. Methods Mice. All animal studies were carried out in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals and approved by the appropriate institutional animal care and use committee. All mice used for functional studies were back-crossed at least nine generations to the 129͞SvEvTac background.

Proceedings of the National Academy of Sciences, 2021

SignificanceThere are no biomarkers for schizophrenia (SCZ), a disorder of dysfunctional neural n... more SignificanceThere are no biomarkers for schizophrenia (SCZ), a disorder of dysfunctional neural networks. We demonstrate that a master regulator of cytoskeleton (“CRMP2”) and, hence, neural circuitry, may form the basis for such a biomarker because its activity is uniquely imbalanced in SCZ patients. We show that SCZ patients are characterized by an excess of active CRMP2 not only in their brains (where it is correlated with dendritic abnormalities) but also in their peripheral blood lymphocytes. The abundance of active CRMP2 and insufficiency of opposing inactive p-CRMP2 likely disrupts neuronal function. Because peripheral blood CRMP2 appears to reflect intracerebral processes, it could form the basis of a rapid, minimally invasive, sensitive, and specific clinical diagnostic aid for SCZ in young patients.

ABSTRACTIntroductionAbnormalities in electroencephalographic (EEG) biomarkers occur in patients w... more ABSTRACTIntroductionAbnormalities in electroencephalographic (EEG) biomarkers occur in patients with schizophrenia and those clinically at high risk for transition to psychosis and are associated with cognitive impairment. While the pathophysiology of schizophrenia remains poorly understood, converging evidence suggests N-methyl-D-aspartate receptor (NMDAR) hypofunction plays a central role and likely contributes to biomarker impairments. Thus, the characterization of such biomarkers is of significant interest for both the early diagnosis of schizophrenia and the development of novel treatments.MethodsWe utilized an established model of chronic NMDAR hypofunction, serine racemase knockout (SRKO) mice. In vivo EEG recording and behavioral analyses were performed on adult male and female SRKO mice and wild-type littermates to determine the impact of chronic NMDAR hypofunction on a battery of translationally-relevant electrophysiological biomarkers.ResultsSRKO mice displayed impairment...

D-serine is the primary NMDA receptor (NMDAR) co-agonist at mature forebrain synapses and is synt... more D-serine is the primary NMDA receptor (NMDAR) co-agonist at mature forebrain synapses and is synthesized by the enzyme serine racemase (SR). However, our understanding of the mechanisms regulating the availability of synaptic D-serine remains limited. Though early studies suggested D-serine is synthesized and released from astrocytes, more recent studies have demonstrated a predominantly neuronal localization of SR. More specifically, recent work intriguingly suggests that SR may be found at the postsynaptic density, yet the functional implications of postsynaptic SR on synaptic transmission are not yet known. Here, we show an age-dependent dendritic and postsynaptic localization of SR and D-serine by immunohistochemistry and electron microscopy in mouse CA1 pyramidal neurons, as well as the presence of SR in human hippocampal synaptosomes. In addition, using a single-neuron genetic approach in SR conditional knockout mice, we demonstrate a cell-autonomous role for SR in regulating ...

Schizophrenia Bulletin, 2018

Alastair Campbell, talking from personal and family experience, and based on years of campaigning... more Alastair Campbell, talking from personal and family experience, and based on years of campaigning and study, urges a rethink of how we view mental health and mental illness.

Nature Neuroscience, 2019

We generated cortical interneurons (cINs) from iPSCs derived from14 healthy controls (HC cINs) an... more We generated cortical interneurons (cINs) from iPSCs derived from14 healthy controls (HC cINs) and 14 patients with schizophrenia (SCZ cINs). Both HC cINs and SCZ cINs were authentic, fired spontaneously, received functional excitatory inputs from host neurons, and induced GABAmediated inhibition in host neurons in vivo. However, SCZ cINs had dysregulated expression of protocadherin genes, which lie within documented SCZ loci. Mice lacking protocadherin α showed defective arborization and synaptic density of prefrontal cortex cINs and behavioral abnormalities. SCZ cINs similarly showed defects in synaptic density and arborization, which were reversed by inhibitors of Protein Kinase C, a downstream kinase in the protocadherin pathway. These findings reveal an intrinsic abnormality in SCZ cINs in the absence of any circuitdriven pathology. They also demonstrate the utility of homogenous and functional populations of a relevant neuronal subtype for probing pathogenesis mechanisms during development.

The FASEB Journal, 1987

There is convincing evidence that acidic amino acids, in particular L-glutamate, or substances co... more There is convincing evidence that acidic amino acids, in particular L-glutamate, or substances containing them serve as the major excitatory neurotransmitters in the brain. At least three distinct receptors mediate the excitatory effects of this class of neurotransmitters. Pharmacological studies with agonists and antagonists of these receptors suggest that they may mediate the neurodegenerative consequences of Huntington's disease, status epilepticus, and hypoxemia, and that glutamate receptor antagonists have clinical potential as anticonvulsants, analgesics, and neuroprotective agents.

Schizophrenia Research, 2018

Deep layer III pyramidal cells in the dorsolateral prefrontal cortex (DLPFC) from subjects with s... more Deep layer III pyramidal cells in the dorsolateral prefrontal cortex (DLPFC) from subjects with schizophrenia and bipolar disorder previously were shown to exhibit dendritic arbor pathology. This study sought to determine whether MARCKS, its regulatory protein dysbindin-1, and two proteins, identified using microarray data, CDC42BPA and ARHGEF6, were associated with dendritic arbor pathology in the DLPFC from schizophrenia and bipolar disorder subjects. Using western blotting, relative protein expression was assessed in the DLPFC (BA 46) grey matter from subjects with schizophrenia (n=19), bipolar disorder (n=17) and unaffected control subjects (n=19). Protein expression data were then correlated with dendritic parameter data obtained previously. MARCKS and dysbindin-1a expression levels did not differ among the three groups. Dysbindin-1b expression was 26% higher in schizophrenia subjects (p=0.01) and correlated inversely with basilar dendrite length (r=−0.31, p=0.048) and the number of spines per basilar dendrite (r=−0.31, p=0.048), but not with dendritic spine density (r=−0.16, p=0.32). The protein expression of CDC42BPA was 33% higher in schizophrenia subjects (p=0.03) but, did not correlate with any dendritic parameter (p>0.05). ARHGEF6 87 kDa isoform expression did not differ among the groups. CDC42BPA expression was not altered in frontal cortex from rats chronically administered haloperidol or clozapine. Dysbindin-1b appears to play a role in dendritic arbor pathology observed previously in the DLPFC in schizophrenia.

Trends in Neurosciences, 2017

As we recently reviewed [1], studies from at least six laboratories now indicate that neurons rat... more As we recently reviewed [1], studies from at least six laboratories now indicate that neurons rather than astrocytes are the major sources for D-serine and preferentially express its synthetic enzyme, serine racemase (SR), in the normal brain [1]. We described how several unforeseen artifacts misled established scientists (including ourselves) into believing that serine racemase and D-serine are localized exclusively to astrocytes and represent prima face

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques, 1986

To define the pathology in cases of non-Alzheimer primary degenerative dementia (non-AD PDD), we ... more To define the pathology in cases of non-Alzheimer primary degenerative dementia (non-AD PDD), we have studied autopsies from four medical centres accessioned in consecutive years since 1976. Neurochemical studies of the basal forebrain-cortical (BF-C) cholinergic system have been conducted in cases from which frozen tissue was available. Twenty-two cases (mean age 70 years, range 47-86) in which the history was consistent with PDD, but which did not meet anatomic criteria for AD, were selected. Approximately 70 cases of PDD, which were accessioned in the same years and met the anatomic criteria for AD, were excluded. The pathologic findings permitted a classification into six groups: Lewy body disease (LBD), 4 cases; Pick's disease, 6 cases; cortical degeneration with motor neuron disease (CDmnd), 2 cases; hippocampal and temporal lobe sclerosis, 3 cases; few or nonspecific abnormalities, 5 cases; other disorders, 2 cases. Our findings suggest that LBD and Pick's disease account for a large proportion of cases of non-AD PDD in the presenile age group, but that a large number of other disorders occasionally present as PDD. Careful examination of the motor systems, as well as cerebral structures relate' to cognitive function, is important in the neuropathologic evaluation. Lesions of the BF-C cholinergic system have been most consistent and severe in LBD, and have not been identified in CDmnd. RESUME: La demence primaire d'origine degenerative sans les caracteristiques pathologiques de la maladie d'Alzheimer. Nous avons etudie du materiel d'autopsies accumule depuis 1974, provenant de quatre centres medicaux, afin de preciser la pathologie chez les cas de demence primaire d'origine degenerative de type non-Alzheimer (DPD non-MA). Nous avons procede a des etudes neurochimiques du systeme cholinergique du cortex de la face inferieure du prosencephale (C-IP) chez les cas pour lesquels du tissu congele etait disponible. Nous avons choisi 22 cas (age moyen 70 ans, ecart 47-86) qui avaient une histoire compatible avec une DPD, mais qui ne correspondaient pas aux criteres anatomiques de la MA. Nous avons exclu a peu pres 70 cas de DPD, accumules au cours des memes annees et qui rencontraient les criteres anatomiques de la MA. Les constatations pathologiques nous ont permis de classifier ces cas en six groupes: la maladie a corps de Lewy (MCL), 4 cas; la maladie de Pick, 6 cas; la degenerescence corticale avec maladie du neurone moteur (DC mnm), 2 cas; la sclerose de l'hippocampe et du lobe frontal, 3 cas; peu d'anomalies ou des anomalies non specifiques, 5 cas; d'autres affections, 2 cas. Ces observations nous autorisent a penser que la MCL et la maladie de Pick sont responsables d'une grande partie des cas de DPD non-MA chez les patients qui sont dans le groupe d'age pre-senile, mais que une grand nombre d'autres affections se prSsentent occasionnellement comme la DPD. II est important d'examiner attentivement les systemes moteurs ainsi que les structures cerebrales en rapport avec les fonctions cognitives lors de ['evaluation du systeme cholinergique du C-IP, qui sont les plus constantes et les plus severes. Ces lesions sont absentes dans la (DC mnm).

Physiological Psychology, 1984

Diseases of the extrapyramidal system usually result in disorders of movement, and the location o... more Diseases of the extrapyramidal system usually result in disorders of movement, and the location of the pathology within this system is critical in the expression of the type of movement disorder. For example, Huntington's disease, which is characterized by degeneration of basal ganglia neurons, is expressed as abnormal involuntary movements (Sanberg & Coyle, in press), whereas, Parkinson's disease, in which there is a loss of the dopamine afferent system to the striatum, results in rigidity and bradykinesia (Barbeau, 1981). Furthermore, Tourette's syndrome, where a hypersensitivity of striatal dopamine receptors has been postulated (Shapiro, Shapiro, & Wayne, 1973; Singer, Butler, Tune, Seifert, & Coyle, 1982), is characterized by chronic fluctuating motor tics and involuntary verbalizations (Singer, 1982). Thus, alterations in the functions of the basal ganglia are evident in many movement disorders. Unfortunately, the role of this important group of telencephalic nuclei in behavior is little understood. Our research interests have been in trying to understand this role for both the developing and mature striatum (Johnson &

Clinical Pharmacology and Therapeutics, 1986

Normal subjects given propranolol increased their plasma t1/2 for infused isoproterenol from 2.68... more Normal subjects given propranolol increased their plasma t1/2 for infused isoproterenol from 2.68 to 6.25 minutes. Propranolol increased plasma norepinephrine (NE) levels only slightly. Propranolol increased the t1/2 of isoproterenol but not that of NE in men with autonomic nervous system degeneration. This suggests that propranolol acts on nonneuronal uptake-2 processes, rather than on uptake-1 mechanisms. alpha-Blockers slow uptake-1 and beta-blockers slow uptake-2 processes. When 27 subjects exercised, those who attained the highest plasma levels of the alpha- and beta-receptor agonist NE also had the briefest apparent t1/2 for NE. Adrenergic receptor blocking drugs slow catecholamine clearance. NE may stimulate its own clearance.