Perineuronal nets protect fast-spiking interneurons against oxidative stress.

A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks. The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress. Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress. These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults. We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display. Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress. In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets. Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress. The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets. Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.

RECHERCHE TRANSLATIONNELLE EN NEUROSCIENCES PSYCHIATRIQUES: DE L'ANIMAL MODELE DE SCHIZOPHRENIE A LA DETECTION D'UNE DESORIENTATION SPATIALE, PRATIQUE OU SYMBOLIQUE CHEZ DES PATIENTS

La mod��lisation, chez l'animal, de maladies psychiatriques telles que la schizophr��nie repose sur diff��rentes d��marches visant �� induire des perturbations c��r��brales similaires �� celles observ��es dans la maladie. Nous avons cherch�� �� ��tudier chez le rat les effets d'une diminution (50%) transitoire en glutathion (GSH) durant le d��veloppement (PND 5 �� PND 16) �� partir de l'implication, chez des adultes, des cons��quences de cette perturbation dans des m��canismes fondamentaux de traitement de l'information sensorielle. Cette th��se ��value et documente les d��ficits de comp��tences de navigation spatiale dans ce mod��le. Nous avons mis en ��vidence des effets comportementaux �� partir de l'identification de diff��rences particuli��res dans des t��ches d'orientation: des difficult��s, chez les rats ayant subi un d��ficit en GSH, �� ��laborer une repr��sentation globale de l'environnement dans lequel ils se d��placent, difficult��s compens��es par une attention particuli��re aux d��tails visuels le composant. Cette strat��gie r��active compensatoire est efficace lorsque les conditions permettent un ajustement continu aux rep��res visuels environnementaux. Elle ne permet cependant pas des pr��dictions et des attentes sur ce qui devrait ��tre rencontr�� et per��u dans une certaine direction, d��s qu'une partie des informations visuelles famili��res dispara��t. Il faudrait pour cela une capacit�� fond��e sur une repr��sentation abstraite, �� distance des modalit��s sensorielles qui en ont permis son ��laboration. Notre th��se soutient que les d��ficits, suppos��s participer �� l'��mergence de certains sympt��mes de la maladie, auraient ��galement des cons��quences sur l'��laboration de la repr��sentation spatiale n��cessaire �� des capacit��s d'orientation effectives et symboliques. - The study of a psychiatric disease such as schizophrenia in an animal model relies on different approaches attempting to replicate brain perturbations similar to those observed in the illness. In the present work, behavioural consequences of a functional deficit in brain connectivity and coordination were assessed in rats with a transitory glutathione (GSH) deficit induced during the postnatal development (PND 5-PND 16) with daily injections of BSO (1- buthionine-(S,R)- sulfoximine). We searched for a theoretical syndrome associating ecologically relevant behavioural adaptive deficits and resulting from the weakening of sensory integration processes. Our results revealed significant and specific deficit of BSO treated rats in spatial orientation tasks designed to test for cognitive mapping abilities. Treated rats behaved as if impaired in the proactive strategies supported by an abstract representation such as a cognitive map. In contrast their performances were preserved whenever the environmental conditions allowed for adaptative reactive strategies, an equivalent of the visual affordances described by Gibson (1958). This supports our thesis that BSO treated rats expressed difficulties in elaborating a global representation of the environment. This deficit was completely - or - partially compensated by the development of an increased attention to the environment's visual details. This compensatory reactive strategy requires a rich environment allowing for continuous adjustment to visual cues. However, such adjustment doesn't allow to predictions and expectancies about what should be met and perceived in a certain direction, when familiar visual spatial cues are missing. Such competencies require orientation based on the use of an abstract spatial representation, independent from the specific sensory modalities that have participated to its elaboration. The impairment of BSO rats such spatial representation could result from a deficit in the integration and organization of perceptual information. Our model leads to the hypothesis that these fundamental deficits might account for certain symptoms of schizophrenia. They would also interfere with in the capacity to elaborate spatial representation necessary for optimal orientation in natural, artificial or symbolic environment.

Drugs, schizotypy and cognition: Cognitive attenuations seem more consistently associated with substance use than schizotypal symptoms

Psychosis is a debilitating disease, causing harm to the individual and society. Since early detection of the disease is associated with a more benign course, factors are warranted that enable the early detection of psychosis. In the present thesis we will be focusing on two potential risk factors, namely schizotypy and drug use. The schizotypy concept, originally developed by Meehl (1962), states that schizophrenia symptoms exist on a spectrum, with symptoms ranging from the most severe in patients with schizophrenia to the least affected individual in the general population. Along the schizophrenia spectrum cognitive impairments are commonly found, for instance reduced hemispheric asymmetry or frontal lobe functions. The second risk factor (drug use), affects similar cognitive functions as those attenuated along the schizophrenia spectrum, and drug use is elevated in schizophrenia and people scoring high on schizotypy. Therefore, we set out to investigate whether cognitive attenuations formerly allocated to schizotypal symptoms could have been influenced by elevated substance use in this population. To test this idea, we assessed various drugs (nicotine, cannabis, mephedrone, general substance dependence) and schizotypy symptoms (O-LIFE), and measured either hemispheric asymmetry of function (left hemisphere dominance for language, and right hemisphere dominance for facial processing) or functions largely relying on the frontal lobes (such as cognitive flexibility, working memory, verbal short-term memory, verbal learning and verbal fluency). Results of all studies suggest that it is mostly drugs, and not schizotypy in general that predict cognitive functioning. Therefore, cognitive attenuations subscribed to schizotypy dimensions are likely to have been affected by enhanced drug use. Future studies should extend the list of potential risk factors (e.g. depression and IQ) to acquire a comprehensive overview of the most reliable predictors of disadvantageous cognitive profiles.

Multi-receptor binding profile of clozapine and olanzapine: a structural study based on the new beta (2) adrenergic receptor template

Schizophrenia is a devastating mental disorder that has a largeimpact on the quality of life for those who are afflicted and isvery costly for families and society.[1] Although the etiology ofschizophrenia is still unknown and no cure has yet beenfound, it is treatable, and pharmacological therapy often producessatisfactory results. Among the various antipsychoticdrugs in use, clozapine is widely recognized as one ofthemost clinically effective agents, even if it elicits significant sideeffects such as metabolic disorders and agranulocytosis. Clozapineand the closely related compound olanzapine are goodexamples ofdrug s with a complex multi-receptor profile ;[2]they have affinities toward serotonin, dopamine, a adrenergic,muscarinic, and histamine receptors, among others.

Validation fran��aise de l'��chelle d'exp��rience temporelle du plaisir [Validation of the Temporal Experience of Pleasure Scale (TEPS) in a French-speaking environment.]

INTRODUCTION: Anhedonia is defined as a diminished capacity to experience pleasant emotion and is commonly included among the negative symptoms of schizophrenia. However, if patients report experiencing a lower level of pleasure than controls, they report experiencing as much pleasure as controls with online measurements of emotion. OBJECTIVE: The Temporal Experience of Pleasure Scale (TEPS) measures pleasure experienced in the moment and in anticipation of future activities. The TEPS is an 18-item self-report measurement of anticipatory (10 items) and consummatory (eight items) pleasure. The goal of this paper is to assess the psychometric characteristics of the French translation of this scale. METHODS: A control sample was composed of 60 women and 22 men, with a mean age of 38.1 years (S.D.: 10.8). Thirty-six were without qualification and 46 with qualified professional diploma. A sample of 21 patients meeting DSM IV-TR criteria for schizophrenia was recruited among the community psychiatry service of the department of psychiatry in Lausanne. They were five women and 16 men; mean age was of 34.1 years (S.D.: 7.5). Ten obtained a professional qualification and 11 were without qualification. None worked in competitive employment. Their mean dose of chlorpromazine equivalent was 431mg (S.D.: 259). All patients were on atypical antipsychotics. The control sample fulfilled the TEPS and the Physical Anhedonia Scale (PAS). The patient sample fulfilled the TEPS and was independently rated on the Calgary Depression Scale and the Scale for Assessment of Negative Symptoms. For comparison with controls, patients were matched on age, sex and professional qualification. This required the supplementary recruitment of two control subjects. RESULTS: Results with the control sample indicate that the TEPS presents an acceptable internal validity with Crombach alphas of 0.84 for the total scale, 0.74 for the anticipatory pleasure scale and 0.79 for the consummatory pleasure scale. The confirmatory factor analysis indicated that the model is well adapted to our data (chi(2)/dl=1.333; df=134; p<0.0006; root mean square residual, RMSEA=0.064). External validity measured with the PAS showed R=-0.27 (p<0.05) for the consummatory scale and R=-0.26 for the total score. Comparisons between patients and matched controls indicated that patients were significantly lower than control on anticipatory pleasure (t=2.7, df(40), 2-tailed p=0.01; cohen's d=0.83) and on total score of the TEPS (t=2.8, df (40), 2-tailed p=0.01; cohen's d=0.87). The two samples did not differ on consummatory pleasure. The anticipatory pleasure factor and the total TEPS showed significant negative correlation with the SANS anhedonia, respectively R=-0.78 (p<0.01) for the anticipatory factor and R=-0.61 (p<0.01) for the total TEPS. There was also a negative correlation between the anticipatory factor and the SANS avolition of R=-0.50 (p<0.05). These correlations were maintained, with partial correlations controlling for depression and chlorpromazine equivalents. CONCLUSION: The results of this validation show that the French version of the TEPS has psychometric characteristics similar to the original version. These results highlight the discrepancy between results of direct or indirect report of experienced pleasure in patients with schizophrenia. Patients may have difficulties in anticipating the pleasure of future enjoyable activities, but not in experiencing pleasure once in an enjoyable activity. Medication and depression do not seems to modify our results, but this should be better controlled in a longitudinal study. The anticipatory versus consummatory pleasure distinction appears to be useful for the development of new psychosocial interventions, tailored to improve desire in patients suffering from schizophrenia. Major limitations of the study are the small size of patient sample and the under representation of men in the control sample.

Synthesis, binding affinity, and molecular docking analysis of new benzofuranone derivative as pontential antipsychotics

The complex etiology of schizophrenia has prompted researchers to develop clozapine-related multitargetstrategies to combat its symptoms. Here we describe a series of new 6-aminomethylbenzofuranones in aneffort to find new chemical structures with balanced affinities for 5-HT2 and dopamine receptors. Throughbiological and computational studies of 5-HT2A and D2 receptors, we identified the receptor serine residuesS3.36 and S5.46 as the molecular keys to explaining the differences in affinity and selectivity betweenthese new compounds for this group of receptors. Specifically, the ability of these compounds to establishone or two H-bonds with these key residues appears to explain their difference in affinity. In addition, wedescribe compound 2 (QF1004B) as a tool to elucidate the role of 5-HT2C receptors in mediating antipsychoticeffects and metabolic adverse events. The compound 16a (QF1018B) showed moderate to high affinitiesfor D2 and 5-HT2A receptors, and a 5-HT2A/D2 ratio was predictive of an atypical antipsychotic profile.

Visual functions in the healthy and schizophrenic brain : from stimulus control to illusory perceptions using electrical neuroimaging

ABSTRACT (FRENCH)Ce travail de th��se bas�� sur le syst��me visuel chez les sujets sains et chez les patients schizophr��nes, s'articule autour de trois articles scientifiques publi��s ou en cours de publication. Ces articles traitent des sujets suivants : le premier article pr��sente une nouvelle m��thode de traitement des composantes physiques des stimuli (luminance et fr��quence spatiale). Le second article montre, �� l'aide d'analyses de donn��es EEG, un d��ficit de la voie magnocellulaire dans le traitement visuel des illusions chez les patients schizophr��nes. Ceci est d��montr�� par l'absence de modulation de la composante PI chez les patients schizophr��nes contrairement aux sujets sains. Cette absence est induite par des stimuli de type illusion Kanizsa de diff��rentes excentricit��s. Finalement, le troisi��me article, ��galement �� l'aide de m��thodes de neuroimagerie ��lectrique (EEG), montre que le traitement des contours illusoires se trouve dans le complexe lat��ro-occipital (LOC), �� l'aide d'illusion �� misaligned gratings ��. De plus il r��v��le que les activit��s d��montr��es pr��c��demment dans les aires visuelles primaires sont dues �� des inf��rences �� top- down ��.Afin de permettre la compr��hension de ces trois articles, l'introduction de ce manuscrit pr��sente les concepts essentiels. De plus des m��thodes d'analyses de temps-fr��quence sont pr��sent��es. L'introduction est divis��e en quatre parties : la premi��re pr��sente le syst��me visuel depuis les cellules retino-corticales aux deux voix du traitement de l'information en passant par les r��gions composant le syst��me visuel. La deuxi��me partie pr��sente la schizophr��nie par son diagnostic, ces d��ficits de bas niveau de traitement des stimuli visuel et ces d��ficits cognitifs. La troisi��me partie pr��sente le traitement des contours illusoires et les trois mod��les utilis��s dans le dernier article. Finalement, les m��thodes de traitement des donn��es EEG seront explicit��es, y compris les m��thodes de temps-fr��quences.Les r��sultats des trois articles sont pr��sent��s dans le chapitre ��ponyme (du m��me nom). De plus ce chapitre comprendra les r��sultats obtenus �� l'aide des m��thodes de temps-fr��quenceFinalement, la discussion sera orient��e selon trois axes : les m��thodes de temps-fr��quence ainsi qu'une proposition de traitement de ces donn��es par une m��thode statistique ind��pendante de la r��f��rence. La discussion du premier article en montrera la qualit�� du traitement de ces stimuli. La discussion des deux articles neurophysiologiques, proposera de nouvelles d'exp��riences afin d'affiner les r��sultats actuels sur les d��ficits des schizophr��nes. Ceci pourrait permettre d'��tablir un marqueur biologique fiable de la schizophr��nie.ABSTRACT (ENGLISH)This thesis focuses on the visual system in healthy subjects and schizophrenic patients. To address this research, advanced methods of analysis of electroencephalographic (EEG) data were used and developed. This manuscript is comprised of three scientific articles. The first article showed a novel method to control the physical features of visual stimuli (luminance and spatial frequencies). The second article showed, using electrical neuroimaging of EEG, a deficit in spatial processing associated with the dorsal pathway in chronic schizophrenic patients. This deficit was elicited by an absent modulation of the PI component in terms of response strength and topography as well as source estimations. This deficit was orthogonal to the preserved ability to process Kanizsa-type illusory contours. Finally, the third article resolved ongoing debates concerning the neural mechanism mediating illusory contour sensitivity by using electrical neuroimaging to show that the first differentiation of illusory contour presence vs. absence is localized within the lateral occipital complex. This effect was subsequent to modulations due to the orientation of misaligned grating stimuli. Collectively, these results support a model where effects in V1/V2 are mediated by "top-down" modulation from the LOC.To understand these three articles, the Introduction of this thesis presents the major concepts used in these articles. Additionally, a section is devoted to time-frequency analysis methods not presented in the articles themselves. The introduction is divided in four parts. The first part presents three aspects of the visual system: cellular, regional, and its functional interactions. The second part presents an overview of schizophrenia and its sensoiy-cognitive deficits. The third part presents an overview of illusory contour processing and the three models examined in the third article. Finally, advanced analysis methods for EEG are presented, including time- frequency methodology.The Introduction is followed by a synopsis of the main results in the articles as well as those obtained from the time-frequency analyses.Finally, the Discussion chapter is divided along three axes. The first axis discusses the time frequency analysis and proposes a novel statistical approach that is independent of the reference. The second axis contextualizes the first article and discusses the quality of the stimulus control and direction for further improvements. Finally, both neurophysiologic articles are contextualized by proposing future experiments and hypotheses that may serve to improve our understanding of schizophrenia on the one hand and visual functions more generally.

D��ficits neuromotors en trastorns de personalitat de l'espectre esquizofr��nic : Una visi�� neuro-anat��mica

Aquest estudi pret��n aprofundir, mitjan��ant t��cniques de neuroimatge, en la cerca de difer��ncies volum��triques, tant en volum de subst��ncia gris com blanca, que presenten els pacients de trastorns de personalitat esquizoide i esquizot��pic amb relaci�� amb un grup control.

A la recherche de sympt��mes de d��sorientation d��pendant d'un d��ficit d'int��gration multisensorielle chez l'animal : un ��clairage sur les m��canismes fondamentaux de la schizophr��nie

Abstract Fundamental research in psychiatric neurosciences assumes that psychiatric disorders are associated with neurobiological factors. Identification of these factors would provide therapeutic targets as well as a better understanding of the relationship between- brain and behaviour in pathological processes. We conducted experiments in an animal model of schizophrenia. Several behavioural tasks were used to evaluate spatial and working memory in these animals. The model is based on glutathione deficit during cerebral development. Indeed, a 50% decrease of glutathione has been reported in prefrontal cortex of patients with schizophrenia. Glutathione is a major antioxidant in the brain and its deficit could lead to abnormal brain connectivity. The glutathione deficit was induced in rats by perinatal (PS-P16) subcutaneous injections with Lbuthionine-(S,R)-sullfoximine (BSO), an inhibitor of glutathione synthesis. This treatment leads to a transitory 50% glutathione levels during brain development. In parallel, we conducted behavioural testing in rats with a medial prefrontal cortex lesion. This allowed us to compare early damage induced by BSO treatment with a focal lesion in adults of a brain area known to present anomalies in schizophrenia. Finally, we conducted a series of experiments in senescent rats to evaluate if cognitive deficits could be related to neurobiological changes. Our results show that an early glutathione deficit provokes cognitive deficits in adulthood. These spatial and working memory deficits resemble the cognitive deficits observed in schizophrenia. The comparison with prefrontal rats revealed that the early brain glutathione deficit provoked more severe cognitive deficits than the prefrontal lesion in adult rats. Moreover, in both cases, we observed a dissociation in memory deficits depending on the type of locomotion that was used in behavioural experiments. Indeed, BSO treated rats as well as prefrontal rats showed place learning or working memory deficits in tasks conducted on dry surfaces where they had to walk. In contrast, they showed no deficit when the same cognitive functions were tested in the water maze. This dissociation might be sustained by a difference in requirement of sensory integration between walking and swimming tasks. R��sum�� La recherche fondamentale en neurosciences psychiatriques repose sur le pr��suppos�� selon lequel les sympt��mes manifest��s dans les troubles psychiatriques auraient des concomitants neurobiologiques. Ceux-ci, une fois identifi��s, offriraient des cibles pour une d��marche th��rapeutique ainsi que des mod��les permettant de mieux comprendre les soubassements biologiques du comportement et des activit��s mentales. Nos exp��riences s'articulent autour de la question de la mod��lisation de la schizophr��nie chez l'animal. Nous avons recherch�� chez ces animaux des troubles cognitifs et sensoriels associ��s �� la schizophr��nie. En effet, chez l'homme comme chez l'animal, la m��moire spatiale et la m��moire de travail d��pendent fortement de la capacit�� d'int��gration et d'organisation des informations sensorielles. Les premi��res exp��riences ont ��t�� men��es suite �� une perturbation p��rinatale du d��veloppement c��r��bral. Celle-ci visait �� reproduire une diminution du taux de glutathion dans le cerveau, des recherches pr��c��dentes ayant observ�� une diminution de 50% du taux de glutathion dans le cortex pr��frontal de patients schizophr��nes. Le glutathion ��tant un antioxydant majeur dans le cerveau, son d��ficit pourrait conduire �� des perturbations de la circuiterie c��r��brale. Nous avons reproduit ce d��ficit chez le rat, par injection de Lbuthionine-(S,R)-sullfoximine (BSO), un inhibiteur de la synth��se du glutathion... Ce traitement a ��t�� administr�� pendant la p��riode p��rinatale (du jour postnatal 5 au jour 16) provoquant une diminution de 50% du taux de glutathion. Nous avons ensuite ��valu�� l��s r��percussions de cette atteinte pr��coce sur le comportement des rats �� l'��ge adulte. Ce mod��le s'inscrit donc dans l'hypoth��se neurod��veloppementale qui associe la schizophr��nie �� une atteinte du d��veloppement c��r��bral normal. Nous avons ensuite conduit des exp��riences similaires chez des rats ayant subi une l��sion du cortex pr��frontal pour comparer les r��percussions du traitement p��rinatal avec une l��sion, �� l'��ge adulte, d'une aire c��r��brale connue pour pr��senter des anomalies chez les patients. Finalement, nous avons ��valu�� si les processus sensoriels et cognitifs pr��c��demment ��tudi��s pouvaient ��galement ��tre affect��s lors du vieillissement normal en recherchant des corr��lats biologiques des d��ficits de m��moire li��s �� l'��ge avanc��. Nos r��sultats montrent que ce d��ficit pr��coce en glutathion peut avoir des r��percussions surale comportement �� l'��ge adulte. On a relev�� une similarit�� avec les d��ficits cognitifs associ��s.�� la schizophr��nie, incluant des d��ficits de m��moire de travail ainsi que des d��ficits de m��moire spatiale. Ces d��ficits ��taient fortement li��s au type de locomotion utilis��e et n'ont ��t�� observ��s que dans les t��ches o�� les animaux devaient rejoindre un but en marchant mais pas dans l��s tests dans lesquels ils devaient localiser une cible en nageant. Les d��ficits induits par la l��sion pr��frontale chez l'adulte ��taient beaucoup plus l��gers que ceux d��coulant de l'atteinte p��rinatale mais pr��sentaient une dissociation analogue en fonction du type de locomotion. De plus, des tests similaires men��s au cours du vieillissement confirment que la m��moire de travail peut ��tre affect��e s��lectivement par le vieillissement dans une t��che o�� les animaux doivent marcher, tout en restant intacte dans le bassin de Morris. Les d��ficits cognitifs li��s au vieillissement ��taient significativement corr��l��s �� des diff��rences de niveaux des prot��ines post-synaptiques PSD95 (postsynaptic density 95). L'ensemble des r��sultats montre que les tests qui sont fr��quemment utilis��s pour ��valuer la m��moire chez l'animal pourraient faire appel �� des processus diff��rents. Cette diff��rence pourrait notamment tenir au niveau d'int��gration sensorielle requis pour r��soudre la t��che, qui est particuli��rement sollicit��e au cours d'une locomotion intermittente.

La r��habilitation psychosociale a l'aube du XXI��me si��cle. I: Principes, population cible et pathologie en cause

The relatively recent development of the psychosocial rehabilitation has its origins mainly in the progress of modern psychopharmacology, the assertion of the rights of the patients and the result of the studies showing that the evolution of persons suffering from severe and persistent mental illnesses can prove to be positive in many cases. In spite of the heterogeneity of the experiences and of the theoretical references, the core principles of the psychosocial rehabilitation imposed themselves. These principles can be classified according to three levels, that of relational ethics, that of the method of intervention and that of the institutional device. A recent study showed that 2.4@1000 of the general adult population of the Canton of Vaud live in sociotherapeutic and rehabilitation accommodations. In this sample, there is a important percentage of relatively young persons (55.3% are under 40). In institutional accommodation there is a majority of patients suffering from major personality disorders and addiction (40.6%), followed by psychotic disorders (37.2%), persistent mood disorders (12.3%), neurotic disorders (6.6%) and psycho-organic disorders (3.3%). In home based rehabilitation, the ratio of patients with psychotic disorders is more important (53.1%). This difference would indicate that people with schizophrenia would have a better social outcome than personality disorders with addiction

Behavioural alteration in chronic pain: are brain glia involved?

Behavioural symptoms such as abnormal emotionality (including anxious and depressive episodes) and cognition (for instance weakened decision-making) are highly frequent in both chronic pain patients and their animal models. The theory developed in the present article posits that alterations in glial cells (astrocytes and microglia) in cortical and limbic brain regions might be the origin of such emotional and cognitive chronic pain-associated impairments. Indeed, in mood disorders (unipolar depression, anxiety disorders, autism or schizophrenia) glial changes in brain regions involved in mood control (prefrontal and cingulate cortices, amygdala and the hippocampus) have been recurrently described. Besides, glial cells have been undoubtedly identified as key actors in the sensory component of chronic pain, owing to the profound phenotypical changes they undergo throughout the sensory pathway. Hence, the possibility arises that brain astrocytes and microglia react in upper brain structures as well, mediating the related mood and cognitive dysfunctions in chronic pain. So far, only very few studies have provided results in this prospect, mainly indirectly in pain-independent researches. Nevertheless, the first scant available data seem to merge in a unified description of a brain glial reaction occurring after chronic peripheral lesion. The present article uses this scarce literature to formulate the provocative theory of a glia-driven mood and cognitive dysfunction in chronic pain, expounding upon its validity and putative therapeutical impact as well as its current limitations and expected future developments.

French version validation of the psychotic symptom rating scales (PSYRATS) for outpatients with persistent psychotic symptoms.

ABSTRACT: BACKGROUND: Most scales that assess the presence and severity of psychotic symptoms often measure a broad range of experiences and behaviours, something that restricts the detailed measurement of specific symptoms such as delusions or hallucinations. The Psychotic Symptom Rating Scales (PSYRATS) is a clinical assessment tool that focuses on the detailed measurement of these core symptoms. The goal of this study was to examine the psychometric properties of the French version of the PSYRATS. METHODS: A sample of 103 outpatients suffering from schizophrenia or schizoaffective disorders and presenting persistent psychotic symptoms over the previous three months was assessed using the PSYRATS. Seventy-five sample participants were also assessed with the Positive And Negative Syndrome Scale (PANSS). RESULTS: ICCs were superior to .90 for all items of the PSYRATS. Factor analysis replicated the factorial structure of the original version of the delusions scale. Similar to previous replications, the factor structure of the hallucinations scale was partially replicated. Convergent validity indicated that some specific PSYRATS items do not correlate with the PANSS delusions or hallucinations. The distress items of the PSYRATS are negatively correlated with the grandiosity scale of the PANSS. CONCLUSIONS: The results of this study are limited by the relatively small sample size as well as the selection of participants with persistent symptoms. The French version of the PSYRATS partially replicates previously published results. Differences in factor structure of the hallucinations scale might be explained by greater variability of its elements. The future development of the scale should take into account the presence of grandiosity in order to better capture details of the psychotic experience.

Skin fibroblast model to study an impaired glutathione synthesis: consequences of a genetic polymorphism on the proteome.

An impaired glutathione (GSH) synthesis was observed in several multifactorial diseases, including schizophrenia and myocardial infarction. Genetic studies revealed an association between schizophrenia and a GAG trinucleotide repeat (TNR) polymorphism in the catalytic subunit (GCLC) of the glutamate cysteine ligase (GCL). Disease-associated genotypes of this polymorphism correlated with a decrease in GCLC protein expression, GCL activity and GSH content. To clarify consequences of a decreased GCL activity at the proteome level, three schizophrenia patients and three controls have been selected based on the GCLC GAG TNR polymorphism. Fibroblast cultures were obtained by skin biopsy and were challenged with tert-butylhydroquinone (t-BHQ), a substance known to induce oxidative stress. Proteome changes were analyzed by two dimensional gel electrophoresis (2-DE) and results revealed 10 spots that were upregulated in patients following t-BHQ treatment, but not in controls. Nine corresponding proteins could be identified by MALDI mass spectrometry and these proteins are involved in various cellular functions, including energy metabolism, oxidative stress response, and cytoskeletal reorganization. In conclusion, skin fibroblasts of subjects with an impaired GSH synthesis showed an altered proteome reaction in response to oxidative stress. Furthermore, the study corroborates the use of fibroblasts as an additional mean to study vulnerability factors of psychiatric diseases.

Genome-wide association analysis of copy number variation in recurrent depressive disorder.

Large, rare copy number variants (CNVs) have been implicated in a variety of psychiatric disorders, but the role of CNVs in recurrent depression is unclear. We performed a genome-wide analysis of large, rare CNVs in 3106 cases of recurrent depression, 459 controls screened for lifetime-absence of psychiatric disorder and 5619 unscreened controls from phase 2 of the Wellcome Trust Case Control Consortium (WTCCC2). We compared the frequency of cases with CNVs against the frequency observed in each control group, analysing CNVs over the whole genome, genic, intergenic, intronic and exonic regions. We found that deletion CNVs were associated with recurrent depression, whereas duplications were not. The effect was significant when comparing cases with WTCCC2 controls (P=7.7 �� 10(-6), odds ratio (OR) =1.25 (95% confidence interval (CI) 1.13-1.37)) and to screened controls (P=5.6 �� 10(-4), OR=1.52 (95% CI 1.20-1.93). Further analysis showed that CNVs deleting protein coding regions were largely responsible for the association. Within an analysis of regions previously implicated in schizophrenia, we found an overall enrichment of CNVs in our cases when compared with screened controls (P=0.019). We observe an ordered increase of samples with deletion CNVs, with the lowest proportion seen in screened controls, the next highest in unscreened controls and the highest in cases. This may suggest that the absence of deletion CNVs, especially in genes, is associated with resilience to recurrent depression.