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1.
Nat Commun ; 12(1): 6187, 2021 10 26.
Article in English | MEDLINE | ID: mdl-34702855

ABSTRACT

Attention-deficit hyperactivity disorder (ADHD) is a common childhood-onset psychiatric disorder characterized by inattention, impulsivity and hyperactivity. ADHD exhibits substantial heritability, with rare monogenic variants contributing to its pathogenesis. Here we demonstrate familial ADHD caused by a missense mutation in CDH2, which encodes the adhesion protein N-cadherin, known to play a significant role in synaptogenesis; the mutation affects maturation of the protein. In line with the human phenotype, CRISPR/Cas9-mutated knock-in mice harboring the human mutation in the mouse ortholog recapitulated core behavioral features of hyperactivity. Symptoms were modified by methylphenidate, the most commonly prescribed therapeutic for ADHD. The mutated mice exhibited impaired presynaptic vesicle clustering, attenuated evoked transmitter release and decreased spontaneous release. Specific downstream molecular pathways were affected in both the ventral midbrain and prefrontal cortex, with reduced tyrosine hydroxylase expression and dopamine levels. We thus delineate roles for CDH2-related pathways in the pathophysiology of ADHD.


Subject(s)
Antigens, CD/genetics , Antigens, CD/metabolism , Attention Deficit Disorder with Hyperactivity/genetics , Attention Deficit Disorder with Hyperactivity/physiopathology , Cadherins/genetics , Cadherins/metabolism , Animals , Antigens, CD/chemistry , Attention Deficit Disorder with Hyperactivity/drug therapy , Attention Deficit Disorder with Hyperactivity/metabolism , Cadherins/chemistry , Child , Dopamine/metabolism , Gene Expression Profiling , Homozygote , Humans , Locomotion/drug effects , Male , Methylphenidate/therapeutic use , Mice , Mutation , Neurons/metabolism , Prefrontal Cortex/metabolism , Protein Conformation , Siblings , Synaptic Transmission/drug effects , Synaptic Vesicles/metabolism , Tyrosine 3-Monooxygenase/metabolism
2.
J Neurochem ; 92(5): 997-1009, 2005 Mar.
Article in English | MEDLINE | ID: mdl-15715651

ABSTRACT

Glutamate in excessive amounts is a major contributor to neuronal degeneration, and its removal is attributed mainly to astrocytes. Traumatic injury to the central nervous system (CNS) is often accompanied by disappearance of astrocytes from the lesion site and failure of the remaining cells to withstand the ensuing toxicity. Microglia that repopulate the lesion site are the usual suspects for causing redox imbalance and inflammation and thus further exacerbating the neurotoxicity. However, our group recently demonstrated that early post-injury activation of microglia as antigen-presenting cells correlates with an ability to withstand injurious conditions. Moreover, we found that T cells reactive to CNS-specific self-antigens protected neurons against glutamate toxicity. Here, we show that antigen-specific autoimmune T cells, by tailoring the microglial phenotype, can increase the ability of microglia-enriched cultures to remove glutamate. This T-cell-mediated effect could not be achieved by the potent microglia-activating agent lipopolysaccharide (LPS), but was dose-dependently reproduced by the Th1 cytokine interferon (IFN)-gamma and significantly reduced by neutralizing anti-IFN-gamma antibodies. Under the same conditions, IFN-gamma had no effect on cultured astrocytes. Up-regulation of glutamate uptake induced by IFN-gamma activation was not accompanied by the acute inflammatory response seen in LPS-activated cultures. These findings suggest that T cells or their cytokines can cause microglia to adopt a phenotype that facilitates rather than impairs glutamate clearance, possibly contributing to restoration of homeostasis.


Subject(s)
Autoimmunity/drug effects , Glutamic Acid/metabolism , Interferon-gamma/pharmacology , Microglia/drug effects , Optic Nerve Injuries/physiopathology , Animals , Antibodies/pharmacology , Antigen-Presenting Cells/metabolism , Antigens, CD/metabolism , Antigens, Differentiation, Myelomonocytic/metabolism , Cells, Cultured , Cyclooxygenase 2 , DNA-Binding Proteins/metabolism , Disease Models, Animal , Dose-Response Relationship, Drug , Flow Cytometry/methods , Glial Fibrillary Acidic Protein/metabolism , Histocompatibility Antigens Class II/metabolism , Immunohistochemistry/methods , Interferon-gamma/immunology , Lipopolysaccharides/pharmacology , Myelin Basic Protein/immunology , Nitric Oxide Synthase/metabolism , Nitric Oxide Synthase Type II , Oligonucleotide Array Sequence Analysis/methods , Oxidative Stress/drug effects , Oxidative Stress/physiology , Phagocytes/metabolism , Prostaglandin-Endoperoxide Synthases/metabolism , RNA, Messenger/metabolism , Rats , Rats, Inbred Lew , Reverse Transcriptase Polymerase Chain Reaction/methods , STAT1 Transcription Factor , Time Factors , Trans-Activators/metabolism
3.
Am J Psychiatry ; 156(10): 1635-7, 1999 Oct.
Article in English | MEDLINE | ID: mdl-10518177

ABSTRACT

OBJECTIVE: The mechanism of action of CO2-induced anxiety is unknown and has been little studied. The authors studied healthy volunteers for the possible influence of serotonin (5-HT) on CO2-induced anxiety. METHOD: Fourteen healthy volunteers received two vital capacity inhalations each of 35% CO2 and of air, preceded once by placebo and once by the 5-HT antagonist metergoline in a double-blind, randomized crossover design. RESULTS: Mean National Institute of Mental Health self-rating anxiety subscale scores increased nonsignificantly after CO2 inhalation; this effect was significantly enhanced by the administration of metergoline. CONCLUSIONS: The authors hypothesize that 5-HT may inhibit CO2-induced anxiety, a function that is lessened by metergoline.


Subject(s)
Anxiety Disorders/chemically induced , Carbon Dioxide/pharmacology , Metergoline/pharmacology , Serotonin Antagonists/pharmacology , Administration, Inhalation , Anxiety Disorders/diagnosis , Anxiety Disorders/physiopathology , Carbon Dioxide/administration & dosage , Cross-Over Studies , Double-Blind Method , Drug Synergism , Humans , Personality Inventory/statistics & numerical data , Placebos , Serotonin/physiology
4.
J Am Acad Dermatol ; 40(5 Pt 2): 822-5, 1999 May.
Article in English | MEDLINE | ID: mdl-10321625

ABSTRACT

Bazex syndrome is a paraneoplastic condition that is most frequently associated with squamous cell carcinoma of the upper aerodigestive tract. The lesions affect acral areas of the skin, including hands, feet, ears, nose, and, to a lesser extent, elbows and knees. Lesions mimic psoriasis and dermatitis. Paronychia and nail dystrophy are frequent. Bullous lesions have been reported only rarely. We report a patient with Bazex syndrome with predominantly bullous lesions that mimicked a primary autoimmune bullous disorder.


Subject(s)
Acrodermatitis/diagnosis , Autoimmune Diseases/diagnosis , Keratosis/diagnosis , Paraneoplastic Syndromes/diagnosis , Skin Diseases, Vesiculobullous/immunology , Acrodermatitis/etiology , Acrodermatitis/pathology , Aged , Autoimmune Diseases/pathology , Carcinoma, Squamous Cell/complications , Diagnosis, Differential , Humans , Keratosis/etiology , Keratosis/pathology , Laryngeal Neoplasms/complications , Male , Nail Diseases/diagnosis , Paraneoplastic Syndromes/etiology , Paraneoplastic Syndromes/pathology , Paronychia/diagnosis , Psoriasis/diagnosis , Skin Diseases, Vesiculobullous/pathology , Vocal Cords/pathology
5.
Mol Plant Microbe Interact ; 5(3): 223-7, 1992.
Article in English | MEDLINE | ID: mdl-1330089

ABSTRACT

To facilitate genetic analyses of Rhizobium meliloti genes that are involved in symbiosis, we determined the map positions of 11 symbiotic loci on the R. meliloti chromosome by using a combination of the Tn5-Mob conjugational transfer method described by Klein et al. (S. Klein, K. Lohmann, G. C. Walker, and E. R. Signer. J. Bacteriol. 174:324-326, 1992) and co-transduction of genetic markers by bacteriophage phi M12. Loci involved in effective nodule formation (fix-379, fix-382, fix-383, fix-385, and fix-388), polysaccharide synthesis (exoR, exoS, exoC, and ndvB), nodule invasion (exoD), and nitrogen regulation (ntrA) were ordered with respect to previously mapped markers and each other. The positions of two other loci, degP and pho-1, were also determined.


Subject(s)
Chromosome Mapping , Sinorhizobium meliloti/genetics , Symbiosis/genetics , Chromosomes, Bacterial , DNA Transposable Elements , Mutagenesis, Insertional
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