Association between the PPP3CC gene, coding for the calcineurin gamma catalytic subunit, and bipolar disorder

<p>Abstract</p> <p>Background</p> <p>Calcineurin is a neuron-enriched phosphatase that regulates synaptic plasticity and neuronal adaptation. Activation of calcineurin, overall, antagonizes the effects of the cyclic AMP activated protein/kinase A. Thus, kinase/phosphatase dynamic balance seems to be critical for transition to long-term cellular responses in neurons, and disruption of this equilibrium should induce behavioral impairments in animal models. Genetic animal models, as well as post-mortem studies in humans have implicated calcineurin dependent calcium and cyclic AMP regulated phosphorylation/dephosphorylation in both affective responses and psychosis. Recently, genetic association between schizophrenia and genetic variation of the human calcineurin A gamma subunit gene (PPP3CC) has been reported.</p> <p>Methods</p> <p>Based on the assumption of the common underlying genetic factor in schizophrenia and bipolar affective disorder (BPAD), we performed association analysis of CC33 and CCS3 polymorphisms of the PPP3CC gene reported to be associated with schizophrenia in a French sample of 115 BPAD patients and 97 healthy controls.</p> <p>Results</p> <p>Carrying 'CT' or 'TT' genotypes of the PPP3CC-CC33 polymorphism increased risk to develop BPAD comparing to carry 'CC' genotype (OR = 1.8 [1.01–3.0]; p = 0.05). For the PPP3CC-CCS3 polymorphism, 'AG' or 'GG' carriers have an increased risk to develop BPAD than 'AA' carriers (OR = 2.8 [1.5–5.2]). The CC33 and CCS3 polymorphisms were observed in significant linkage disequilibrium (D' = 0.91, r²= 0.72). Haplotype frequencies were significantly different in BPAD patients than in controls (p = 0.03), with a significant over-transmission of the 'TG' haplotype in BPAD patients (p = 0.001).</p> <p><b>Conclusion:</b></p> <p>We suggest that the PPP3CC gene might be a susceptibility gene for BPAD, in accordance with current neurobiological hypotheses that implicate dysregulation of signal-transduction pathways, such as those regulated by calcineurin, in the etiology of affective disorders.</p

Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals

Copy number variants (CNV) are established risk factors for neurodevelopmental disorders with seizures or epilepsy. With the hypothesis that seizure disorders share genetic risk factors, we pooled CNV data from 10,590 individuals with seizure disorders, 16,109 individuals with clinically validated epilepsy, and 492,324 population controls and identified 25 genome-wide significant loci, 22 of which are novel for seizure disorders, such as deletions at 1p36.33, 1q44, 2p21-p16.3, 3q29, 8p23.3-p23.2, 9p24.3, 10q26.3, 15q11.2, 15q12-q13.1, 16p12.2, 17q21.31, duplications at 2q13, 9q34.3, 16p13.3, 17q12, 19p13.3, 20q13.33, and reciprocal CNVs at 16p11.2, and 22q11.21. Using genetic data from additional 248,751 individuals with 23 neuropsychiatric phenotypes, we explored the pleiotropy of these 25 loci. Finally, in a subset of individuals with epilepsy and detailed clinical data available, we performed phenome-wide association analyses between individual CNVs and clinical annotations categorized through the Human Phenotype Ontology (HPO). For six CNVs, we identified 19 significant associations with specific HPO terms and generated, for all CNVs, phenotype signatures across 17 clinical categories relevant for epileptologists. This is the most comprehensive investigation of CNVs in epilepsy and related seizure disorders, with potential implications for clinical practice

Etudes des altérations comportementales reliées à l'hyperdopaminergie chez les souris DAT KOs (interaction avec le système cholinergique)

PARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Geographic stroke accessibility in Rhône: new modeling methods

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L'accident vasculaire cérébral : caractériser les inégalités de répartition en vallée du Rhône à l'aide d'outils géographiques

International audienceStroke is a sudden and brutal illness that can have serious consequences. The prevalence of the pathology is known, but its spatial incidence is less studied. The objective of this study is to describe the spatial distribution of stroke occurrences and to characterise its spatial distribution patterns in order to identify possible unequal territories. This distribution is then analysed using different territorial (socio-economic, structural, environmental) and temporal (calendar and climatic) variables in order to understand the causes of stroke over-representation in certain locations. The analyses conducted throughout this work were based on data from the Rhône Valley Emergency Network’s (RESUVal) registry of thrombolysed strokes, as well as on data from the STROKE 69 cohort in the Rhône. This work is intended to be highly operational, making it possible to propose ways of improving stroke management in the region in terms of public policies to raise awareness among populations at risk of stroke.L’accident vasculaire cérébral (AVC) est une pathologie soudaine et brutale pouvant entraîner de graves séquelles. La prévalence de la pathologie est connue, mais son incidence spatiale est moins étudiée. L’objectif de cette étude est de décrire la répartition spatiale des occurrences d’AVC et de caractériser les modèles de distribution spatiale d’AVC afin d’identifier d’éventuels territoires inégalitaires. Cette répartition est ensuite analysée à l’aide de différentes variables territoriales (socio-économiques, structurelles, environnementales) et temporelles (calendaires et climatiques) afin de comprendre les causes de la surreprésentation des AVC en certains endroits. Les analyses menées tout au long de ce travail se sont appuyées sur les données du registre des AVC thrombolysés du Réseau des urgences de la vallée du Rhône (RESUVal), ainsi que sur les données de la cohorte STROKE 69 dans le Rhône. Ce travail se veut très opérationnel, permettant de proposer des axes pour améliorer territorialement la prise en charge de l’AVC, notamment en termes de politiques publiques permettant de sensibiliser les populations à risque de survenue d’un AVC

Interactions between the cannabinoid and dopaminergic systems: Evidence from animal studies

International audienceThere is a prominent role of the cannabinoid system to control basal ganglia function, in respect to reward, psychomotor function and motor control. Cannabinoid dysregulations might have a pathogenetic role in dopamine- and basal ganglia related neuropsychiatric disorders, such as drug addiction, psychosis, Parkinson's disease and Huntington's disease. This review highlights interactions between cannabinoids, and dopamine, to modulate neurotransmitter release and synaptic plasticity in the context of drug addiction, psychosis and cognition. Modulating endocannabinoid function, as a plasticity based therapeutic strategy, in the above pathologies with particular focus on cannabinoid receptor type 1 (CB1 receptor) antagonists/inverse agonists, is discussed. On the basis of the existing literature and of new experimental evidence presented here, CBI receptor antagonists might be beneficial in disease states associated with hedonic dysregulation, and with cognitive dysfunction in particular in the context of psychosis. It is suggested that this effects might be mediated via a hyperglutamatergic state through metabotropic glutamate activation. Indications for endocannabinoid catabolism inhibitors in psychiatric disorders, that might be CB1 receptor independent and might involve TRPV1 receptors, are also discussed

Analyse du lien entre AVC et niveau de vie dans le Rhône

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