Neuropathological and Reelin Deficiencies in the Hippocampal Formation of Rats Exposed to MAM; Differences and Similarities with Schizophrenia

Adult rats exposed to methylazoxymethanol (MAM) at embryonic day 17 (E17) consistently display behavioral characteristics similar to that observed in patients with schizophrenia and replicate neuropathological findings from the prefrontal cortex of psychotic individuals. However, a systematic neuropathological analysis of the hippocampal formation and the thalamus in these rats is lacking. It is also unclear if reelin, a protein consistently associated with schizophrenia and potentially involved in the mechanism of action of MAM, participates in the neuropathological effects of this compound. Therefore, a thorough assessment including cytoarchitectural and neuromorphometric measurements of eleven brain regions was conducted. Numbers of reelin positive cells and reelin expression and methylation levels were also studied.Compared to untreated rats, MAM-exposed animals showed a reduction in the volume of entorhinal cortex, hippocampus and mediodorsal thalamus associated with decreased neuronal soma. The entorhinal cortex also showed laminar disorganization and neuronal clusters. Reelin methylation in the hippocampus was decreased whereas reelin positive neurons and reelin expression were unchanged.Our results indicate that E17-MAM exposure reproduces findings from the hippocampal formation and the mediodorsal thalamus of patients with schizophrenia while providing little support for reelin's involvement. Moreover, these results strongly suggest MAM-treated animals have a diminished neuropil, which likely arises from abnormal neurite formation; this supports a recently proposed pathophysiological hypothesis for schizophrenia

The Self-Assessment Scale of Cognitive Complaints in Schizophrenia: A validation study in Tunisian population

<p>Abstract</p> <p>Background</p> <p>Despite a huge well-documented literature on cognitive deficits in schizophrenia, little is known about the own perception of patients regarding their cognitive functioning. The purpose of our study was to create a scale to collect subjective cognitive complaints of patients suffering from schizophrenia with Tunisian Arabic dialect as mother tongue and to proceed to a validation study of this scale.</p> <p>Methods</p> <p>The authors constructed the Self-Assessment Scale of Cognitive Complaints in Schizophrenia (SASCCS) based on a questionnaire covering five cognitive domains which are the most frequently reported in the literature to be impaired in schizophrenia. The scale consisted of 21 likert-type questions dealing with memory, attention, executive functions, language and praxia. In a second time, the authors proceeded to the study of psychometric qualities of the scale among 105 patients suffering from schizophrenia spectrum disorders (based on DSM- IV criteria). Patients were evaluated using the Positive and Negative Syndrome Scale (PANSS), the Global Assessment Functioning Scale (GAF scale) and the Calgary Depression Scale (CDS).</p> <p>Results</p> <p>The scale's reliability was proven to be good through Cronbach alpha coefficient equal to 0.85 and showing its good internal consistency. The intra-class correlation coefficient at 11 weeks was equal to 0.77 suggesting a good stability over time. Principal component analysis with Oblimin rotation was performed and yielded to six factors accounting for 58.28% of the total variance of the scale.</p> <p>Conclusion</p> <p>Given the good psychometric properties that have been revealed in this study, the SASCCS seems to be reliable to measure schizophrenic patients' perception of their own cognitive impairment. This kind of evaluation can't substitute for objective measures of cognitive performances in schizophrenia. The purpose of such an evaluation is to permit to the patient to express his own well-being and satisfaction of quality of life.</p

Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies

Mapping genomic loci prioritises genes and implicates synaptic biology in schizophrenia

Schizophrenia has a heritability of 60–80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies

Homéogènes et troubles psychiatriques d origine neurodéveloppementale (caractérisation comportementale d un modèle de souris haplo-insuffisante pour Otx2)

Le spectre des troubles neurodéveloppementaux regroupe l ensemble des pathologies dont l origine est en rapport avec une anomalie du développement cérébral.L existence d un important recouvrement épidémiologique, clinique et génétique est en faveur d un continuum entre ces pathologies qui pourraient partager des étiologies communes aussi bien génétiques qu environnementales.Les homéogènes codent pour des facteurs de transcription. Ils sont exprimés précocement pendant l embryogénèse et coordonnent le développement cérébral. Le résultat le plus robuste de la revue de la littérature, que nous avons réalisé, entre les pathologies neurodéveloppementales et les mutations des homéogènes est l association entre deux polymorphismes d Engrailed 2 et l autisme.L homéogène Otx2 est impliqué dans l organisation et la différenciation de structures cérébrales et de systèmes de neurotransmission pour lesquels des anomalies ont été décrites dans plusieurs pathologies psychiatriques. Nous avons évalué dans le modèle murin Otx2GFP/+, où un allèle du gène a été inactivé, l apparition de traits comportementaux en rapport avec la cognition, l anxiété, la dépression, la psychose ainsi que les capacités motrices et sociales. Nous avons mis en évidence au cours de ces tests que les souris hétérozygotes présentaient un niveau d anxiété plus faible que les sauvages ainsi qu une vulnérabilité pour les troubles psychotiques. Ces résultats permettent de progresser dans la connaissance de l implication des homéogènes dans la physiopathologie de ces troubles et ouvrent de nouvelles perspectives de recherchePARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocSudocFranceF

Mu-opioid antagonism in the treatment of cannabis use disorder

International audienceno abstrac

Perinatal Exposure to Environmental Endocrine Disruptors in the Emergence of Neurodevelopmental Psychiatric Diseases: A Systematic Review

Background: Exposure to endocrine disruptors is on the rise, with new compounds regularly incriminated. In animals and humans, this exposure during critical developmental windows has been associated with various developmental abnormalities, including the emergence of psychiatric disorders. We aimed to review the association between perinatal endocrine disruptor exposure and neurodevelopmental disorders in humans, focusing on cognitive and psychiatric disorders. Methods: We performed a systematic review with key words referring to the fields of neurodevelopment and endocrine disruptors. We reviewed 896 titles, choosing studies on the basis of titles and abstracts. We searched through the methodology sections to find perinatal exposure and neurodevelopmental disorders, following the categories indicated in the Diagnostic and Statistic Manual of Mental Disorders (5th edition). References in some studies brought us to a total of 47 studies included here. Results: Convergent studies report an association between exposure to endocrine disruptors and autism spectrum disorder, attention-deficit hyperactivity disorder, global developmental delay, intellectual disability, communication disorders and unspecified neurodevelopmental disorders. Conclusion: Sufficient data exist to report that exposure to some endocrine disruptors is a risk factor for the emergence of neurodevelopmental disorders. Studying endocrine disruptor exposure in humans is still associated with some limits that are difficult to overcome

Génétique et épigénétique de la schizophrénie et des psychoses

La schizophrénie et les autres troubles psychotiques sont des pathologies fréquentes et hétérogènes dont la physiopathologie reste encore mal comprise. Les avancées récentes en biologie moléculaire ont montré que plusieurs types de variations génétiques étaient impliqués dans ces troubles. Ces facteurs peuvent correspondre à des variants rares à forte pénétrance ou à des variants communs de faible pénétrance. Ces variants peuvent également se combiner entre eux. En pratique clinique, la recherche de ces variants peut aider à la prise en charge et au conseil génétique dans certains cas. S’il est indéniable que des facteurs génétiques sont impliqués dans ces troubles, ceux-ci ne suffisent pas à eux seuls à expliquer le phénotype. En effet, les psychoses sont des maladies complexes qui nécessitent des interactions entre gène(s) et facteurs d’environnement. Le substrat moléculaire de ces interactions pourrait reposer sur l’épigénétique qui regroupe la méthylation de l’ADN, les modifications des histones et les micro-ARN. L’implication de ces trois mécanismes a pu être décrite dans le champ de la schizophrénie mais les études sont encore trop rares et disparates pour faire émerger des conclusions définitives. En outre, ces mécanismes génétiques et épigénétiques sont imbriqués puisque l’épigénome est régulé par des gènes. Les bases génétiques et épigénétiques des psychoses sont importantes à explorer car elles ouvrent la voie à une redéfinition des diagnostics sur des bases biologiques et qu’elles constituent de possibles pistes thérapeutiques

A Multi-Agent Model for Countering Terrorism

The rise of terrorism over the past decade did not only hinder the development of some countries, but also it continues to destroy humanity. To face this concept of an emerging crisis, every country and every citizen is responsible for the fight against terrorism. As conventional plans became useless against terrorism, governments are required to establish innovative concepts and technologies to support units in this asymmetric war. In this paper, we propose a new multi-agent model for counter-terrorism characterized by a methodical process and a flexibility to handle different contingency scenarios. The division of labour in our multi-agent model improves decision making and the structuring of organisational plans