Treatment implications of the emerging molecular classification system for melanoma.

Melanoma is an aggressive disease with few standard treatment options. The conventional classification system for this disease is based on histological growth patterns, with division into four subtypes: superficial spreading, lentigo maligna, nodular, and acral lentiginous. Major limitations of this classification system are absence of prognostic importance and little correlation with treatment outcomes. Recent preclinical and clinical findings support the notion that melanoma is not one malignant disorder but rather a family of distinct molecular diseases. Incorporation of genetic signatures into the conventional histopathological classification of melanoma has great implications for development of new and effective treatments. Genes of the mitogen-associated protein kinase (MAPK) pathway harbour alterations sometimes identified in people with melanoma. The mutation Val600Glu in the BRAF oncogene (designated BRAF(V600E)) has been associated with sensitivity in vitro and in vivo to agents that inhibit BRAF(V600E) or MEK (a kinase in the MAPK pathway). Melanomas arising from mucosal, acral, chronically sun-damaged surfaces sometimes have oncogenic mutations in KIT, against which several inhibitors have shown clinical efficacy. Some uveal melanomas have activating mutations in GNAQ and GNA11, rendering them potentially susceptible to MEK inhibition. These findings suggest that prospective genotyping of patients with melanoma should be used increasingly as we work to develop new and effective treatments for this disease.

Neurodevelopment outcome of newborns with cerebral subependymal pseudocysts at 18 and 46 months: a prospective study.

OBJECTIVES: Subependymal pseudocysts (SEPC) are cerebral periventricular cysts located on the floor of the lateral ventricle and result from regression of the germinal matrix. They are increasingly diagnosed on neonatal cranial ultrasound. While associated pathologies are reported, information about long-term prognosis is missing, and we aimed to investigate long-term follow-up of these patients. STUDY DESIGN: Newborns diagnosed with SEPC were enrolled for follow-up. Neurodevelopment outcome was assessed at 6, 18 and 46 months of age. RESULTS: 74 newborns were recruited: we found a high rate of antenatal events (63%), premature infants (66% <37 weeks, 31% <32 weeks) and twins (30%). MRI was performed in 31 patients, and cystic periventricular leukomalacia (c-PVL) was primarily falsely diagnosed in 9 of them. Underlying disease was diagnosed in 17 patients, 8 with congenital cytomegalovirus (CMV) infection, 5 with genetic and 4 with metabolic disease. Neurological examination (NE) at birth was normal for patients with SEPCs and no underlying disease, except one. Mean Developmental Quotient and IQ of these patients was 98.2 (±9.6SD; range 77-121), 94.6 (±14.2SD; 71-120) and 99.6 (±12.3SD; 76-120) at 6, 18 and 46 months of age, respectively, with no differences between the subtypes of SEPC. A subset analysis showed no outcome differences between preterm infants with or without SEPC, or between preterm of <32 GA and ≥32 GA. CONCLUSIONS: Neurodevelopment of newborns with SEPC was normal when no underlying disease was present. This study suggests that if NE is normal at birth and congenital CMV infection can be excluded, then no further investigations are needed. Moreover, it is crucial to differentiate SEPC from c-PVL which carries a poor prognosis.

Fecundity versus offspring size in the greater white-toothed shrew Crocidura russula

1. The relationships between female body mass (WWal)i, tter size (m), juvenile growth rate (G) and mass at weaning (W20) were examined by monitoring natural litters in 29 greater white-toothed shrews, Crocidura russula (Hermann 1780). The trade-offs between m and G or W20 were further investigated by manipulating litter sizes: each of seven females reared four litters of 2, 4, 6 and 8 offspring. 2. Offspring mass at weaning (W20) exhibited a large variance, most of which could be attributed (ANCOVA on manipulated litters) to two effects: a litter-size effect, and a female individual effect, referred to as 'female quality'. 3. Litter size explained 68% of the variance in W20 among manipulated litters (linear regression). The limited milk supply was probably responsible for this effect, because litter size depressed growth rate during the first half of the lactation period (G1), but not during the weaning stage (G2). 4. Among non-manipulated litters, litter size correlated positively with maternal body mass (Wa), so that large females tended to produce small juveniles. This correlation between m and Wa is seen as the result of a body-mass dependence in the cost of raising a litter of a given size, during either pregnancy or lactation. 5. Differences in 'female quality' explained 16% of the variance in W20 among manipulated litters. This factor did not affect GI and may thus relate to differences among offspring of different females in their rates of processing milk and/or external food during late lactation. 6. 'Female quality' was independent of both body mass and litter size: larger females did not produce larger offspring when controlled for litter size, while higher-quality females did not produce larger litters. 7. Our results support the hypothesis that most variance in adult and juvenile body masses is non-genetic, and stems from the trade-off between litter size and offspring size.

Para-arterial sparing phenotype in Leber congenital amaurosis associated with homozygous p.R108X SPATA-7 mutation

Purpose: To describe the genotype/phenotype correlation associated with homozygous p.R108X mutation in the SPATA7 gene. Methods: A consanguineous nuclear family of Ethiopian origin was ascertained for genotypic and phenotypic characterization, including fundus photography, fundus autofluorescence (FAF), and full-field ERG. Molecular diagnosis was performed using a microarray. Results: Two of the 5 family members were affected with LCA. A homozygous c.322C>T (p.R108X) mutation in exon 5 of SPATA-7 was identified in both of them. The patients were 4 and 11 years old, respectively. Fundus examination revealed an unremarkable macular area, but optic nerve pallor, attenuated vascular calibre and deep retinal nummular deposits with para-arterial sparing predominant in the midperiphery. FAF showed multiples areas of hyperautofluorescence, corresponding to the deep retinal deposits. ERG was not recordable in the young patient, and showed severe rods/cones dysfunction in the older one. Conclusions: The literature describing genotype/phenotype correlation of SPATA-7 mutations in Leber congenital amaurosis (LCA) is still limited. We report the occurrence of para-arterial sparing in two sibs with SPATA7-linked LCA which may represent a clinical marker of this condition.

Gene-disease network analysis reveals functional modules in mendelian, complex and environmental diseases

AbstractBACKGROUND: Scientists have been trying to understand the molecular mechanisms of diseases to design preventive and therapeutic strategies for a long time. For some diseases, it has become evident that it is not enough to obtain a catalogue of the disease-related genes but to uncover how disruptions of molecular networks in the cell give rise to disease phenotypes. Moreover, with the unprecedented wealth of information available, even obtaining such catalogue is extremely difficult.PRINCIPAL FINDINGS: We developed a comprehensive gene-disease association database by integrating associations from several sources that cover different biomedical aspects of diseases. In particular, we focus on the current knowledge of human genetic diseases including mendelian, complex and environmental diseases. To assess the concept of modularity of human diseases, we performed a systematic study of the emergent properties of human gene-disease networks by means of network topology and functional annotation analysis. The results indicate a highly shared genetic origin of human diseases and show that for most diseases, including mendelian, complex and environmental diseases, functional modules exist. Moreover, a core set of biological pathways is found to be associated with most human diseases. We obtained similar results when studying clusters of diseases, suggesting that related diseases might arise due to dysfunction of common biological processes in the cell.CONCLUSIONS: For the first time, we include mendelian, complex and environmental diseases in an integrated gene-disease association database and show that the concept of modularity applies for all of them. We furthermore provide a functional analysis of disease-related modules providing important new biological insights, which might not be discovered when considering each of the gene-disease association repositories independently. Hence, we present a suitable framework for the study of how genetic and environmental factors, such as drugs, contribute to diseases.AVAILABILITY: The gene-disease networks used in this study and part of the analysis are available at http://ibi.imim.es/DisGeNET/DisGeNETweb.html#Download

Uric acid and cardio-metabolic risk factors : an epidemiological approach

The role of serum uric acid (SUA) in cardio-metabolic conditions has long been contentious. It is still unclear if SUA is an independent risk factor or marker of cardio-metabolic conditions and most observed associations are not necessarily causal. This study aimed to further understand and explore the causal role of SUA in cardio-metabolic conditions using genetic and non-genetic epidemiological methods in population-based data. In the first part of this study, we found moderate to high heritability estimates for SUA and fractional excretion of urate (FEUA) suggesting the role of genetic factors in the etiology of hyperuricemia. With regards to the role of SUA on inflammatory markers (IMs), a strong positive association of SUA with C-reactive protein (CRP) and a weaker positive association with tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) was observed, which was in part mediated by body mass index (BMI). These findings suggest that SUA may have a role in sterile inflammation. In view of the inconsistency surrounding the causal nature and direction of the relation between SUA and adiposity, we applied a bidirectional Mendelian randomization approach using genetic variants to decipher the association. The finding that elevated SUA is a consequence rather than a cause of adiposity was not totally unexpected and is compatible with the hypothesis that hyperinsulinemia, accompanying obesity, enhances renal proximal tubular reabsorption of uric acid. The fourth part of this study examined the relationship between SUA and blood pressure (BP) in young adults. The association between SUA and BP, significant only in females, was strongly attenuated upon adjustment for BMI. The possibility that BMI lies in the causal pathway may explain the attenuation observed in the associations of SUA with BP and IMs. Finally, a significant hockey-stick shaped association of SUA with social phobia in our data suggests a protective effect of SUA only up to a certain concentration. Although our study findings have shed some light on the uncertainty underlying the pathophysiology of SUA, more compelling evidence using longitudinal designs, randomized controlled trials and the use of robust genetic tools is warranted to increase our understanding of the clinical significance of SUA.

Mycobacterium tuberculosis-specific CD8 T cells are functionally and phenotypically different between latent infection and active disease

Purpose/Objective: Tuberculosis (TB) is the second worldwide leading cause of death from an infectious disease after HIV infection. Protective immunity to Mycobacterium tuberculosis (Mtb) remains poorly understood and the role of Mtb-specific CD8 T-cells is controversial. We performed comprehensive functional and phenotypic characterizations of Mtb-specific CD8 T-cell responses in 273 subjects with either latent Mtb infection (LTBI) or active TB disease (TB) to assess their profile and relevance in TB. Materials and methods: Using multi-parametric flow cytometry, we assessed Mtb-specific CD8 T-cell functional (production of IFNgamma, IL-2 and TNF-alpha; proliferation capacity and cytotoxicity) and phenotypic (T-cell differentiation and exhaustion) profiles in cells isolated from peripheral blood and correlated these profiles with distinct clinical presentations. Results: Mtb-specific CD8 T-cells were detected in most TB patients and few LTBI subjects (65% and 15%, respectively; P < 0.00001) and were of similar magnitude with a comparable cytokines profile (IFNg+TNFa+IL2-) in both groups. Mtb-specific CD8 T-cells were mostly TEMRA (CD45RA+ CCR7-) co-expressing 2B4 and CD160 in LTBI subjects and mostly TEM (CD45RA-CCR7-) lacking PD-1/ CD160/2B4 in TB patients. Furthermore, Mtb-specific CD8 T-cells mostly expressed very little perforin and granulysin but contained granzymes A and B or lacked all these cytotoxic markers in TB and LTBI subjects, respectively. However, in vitro expanded Mtb-specific CD8 T-cells acquired perforin, granulysin and granzymes. Finally, Mtb-specific CD8 T-cell responses were more robust and prone to proliferate in patients with extrapulmonary compared to pulmonary TB. Conclusions: The clinical status and TB presentation are associated to specific profiles of Mtb-specific CD8 T-cell responses, thus indicating distinct dynamics between the mycobacteria, the CD8 T-cell response and the clinical outcome. Our data shed light on the controversial reached by studies performed in human and animal models, thus advancing the current knowledge on the complex dynamic of TB immunity.

Imazaquin sorption in surface and subsurface soil samples

The objective of this work was to study the sorption and desorption of imazaquin, in surface and subsurface soil samples from Brazil. Sorption and desorption steps were carried out using batch equilibration and high performance liquid chromatography analytical routines. The value of Kf,ads was positively correlated with clay content, and negatively correlated with pH of supernatant. Samples from Typic Haplustox, clayey soil profile having high clay content, provided higher Kf,ads values, and negative correlation with organic carbon, silt content, cation exchange capacity and pH.

Testing the effects of genetic crossing distance on embryo survival within a metapopulation of brown trout (Salmo trutta)

Predicting progeny performance from parental genetic divergence can potentially enhance the efficiency of supportive breeding programmes and facilitate risk assessment. Yet, experimental testing of the effects of breeding distance on offspring performance remains rare, especially in wild populations of vertebrates. Recent studies have demonstrated that embryos of salmonid fish are sensitive indicators of additive genetic variance for viability traits. We therefore used gametes of wild brown trout (Salmo trutta) from five genetically distinct populations of a river catchment in Switzerland, and used a full factorial design to produce over 2,000 embryos in 100 different crosses with varying genetic distances (FST range 0.005-0.035). Customized egg capsules allowed recording the survival of individual embryos until hatching under natural field conditions. Our breeding design enabled us to evaluate the role of the environment, of genetic and nongenetic parental contributions, and of interactions between these factors, on embryo viability. We found that embryo survival was strongly affected by maternal environmental (i.e. non-genetic) effects and by the microenvironment, i.e. by the location within the gravel. However, embryo survival was not predicted by population divergence, parental allelic dissimilarity, or heterozygosity, neither in the field nor under laboratory conditions. Our findings suggest that the genetic effects of inter-population hybridization within a genetically differentiated meta-population can be minor in comparison to environmental effects.

Mice with chronic GSH deficit display phenotypical anomalies that resemble key aspects of schizophrenia

ABSTRACTSchizophrenia is a major psychiatric disorder occurring with a prevalence of 1% in the worldwide population. It develops progressively with psychosis onset in late adolescence or earlyadulthood. The disorder can take many different facets and has a highly diffuse anddistributed neuropathology including deficits in major neurotransmitter systems,myelination, stress regulation, and metabolism. The delayed onset and the heterogeneouspathology suggest that schizophrenia is a developmental disease that arises from interplayof genetic and environmental factors during sensitive periods. Redox dysregulation due to animbalance between pro-oxidants and antioxidant defence mechanisms is among the riskfactors for schizophrenia. Glutathione (GSH) is the major cellular redox regulator andantioxidant. Levels of GSH are decreased in cerebrospinal fluid, prefrontal cortex and postmortemstriatum of schizophrenia patients. Moreover, polymorphisms of the key GSHsynthesizingenzyme, glutamate-cysteine ligase, modifier (GCLM) subunit, are associatedwith the disease, suggesting that GSH deficit is of genetic origin. Here we used miceknockout (KO) for the GCLM gene, which display chronic GSH deficit (~70 to 80% decrease)to investigate the direct link between redox dysregulation and schizophrenia. Accordingly,we evaluated whether GCLM KO compared to normal wildtype mice display behavioralchanges that relate to schizophrenia symptoms and whether their brains showmorphological, functional or metabolic alterations that resemble those in patients.Moreover, we exposed pubertal GCLM mice to repeated mild stress and measured theirhormonal and behavioral stress reactivity. Our data show that chronic GSH deficit isassociated with altered emotion- and stress-related behaviors, deficient prepulse inhibition,pronounced amphetamine-induced hyperlocomotion but normal spatial learning andworking memory. These changes represent important schizophrenia endophenotypes.Moreover, this particular pattern of change indicates impairment of the ventralhippocampus (VH) and related circuitry as opposed to the dorsal hippocampus (DH), which isimplicated in spatial information processing. This is consistent with a selective deficit ofparvalbumin positive interneurons and gamma oscillation in the VH but not DH. Increasedlevels of circulating stress hormones in KO mice following pubertal stress corroborate VHdysfunction as it is involved in negative feedback control of the stress response. VHstructural and functional deficits are frequently found in the schizophrenic brain. Metabolicevaluation of the developing GCLM KO anterior cortex using in vivo magnetic resonancespectroscopy revealed elevated glutamine (Gln), glutamate (Glu), Gln/Glu and N-acetylaspartate(NAA) during the pre-pubertal period. Similar changes are reported in earlyschizophrenia. Overall, we observe phenotypic anomalies in GSH deficient GCLM KO micethat correspond to major schizophrenia endophenotypes. This supports an important rolefor redox dysregulation in schizophrenia and validates the GCLM KO mouse as model for thedisease. Moreover, our results indicate that puberty may be a sensitive period for redoxsensitivechanges highliting the importance of early intervention. Gln, Gln/Glu, Glu and NAAmay qualify as early metabolic biomarkers to identify young at-risk individuals. Since chronictreatment with NAC normalized most metabolic changes in GCLM KO mice, NAC may be oneadjunct treatment of choice for early intervention in patients.RESUMELa schizophrénie est une maladie psychiatrique majeure avec une prévalence de 1% dans lapopulation. Son développement est progressif, les premières psychoses apparaissant àl'adolescence ou au début de l'âge adulte. La maladie a plusieurs présentations et uneneuropathologie étendue, qui inclut des déficits neurochimiques, métaboliques, de lamyélination et de la régulation du stress. L'émergence tardive et l'hétérogénéité de lapathologie suggèrent que la schizophrénie est une maladie développementale, favorisée pardes facteurs génétiques et environnementaux durant des périodes sensibles. La dérégulationrédox, due à un déséquilibre entre facteurs pro-oxidantes et défenses anti-oxidantes,constitue un facteur de risque. Le glutathion (GSH) est le principal régulateur rédox et antioxidantdes cellules, ses taux sont diminués dans le liquide céphalorachidien, le cortexpréfrontal et le striatum de patients. De plus, des variations du gène codant la sous-unitémodulatrice (GCLM) de la glutamate-cystéine ligase, enzyme de synthèse du GSH, sontassociés la maladie, suggérant que le déficit observé chez les patients est d'originegénétique. Nous avons donc utilisé des souris ayant une délétion du gène GCLM (KO), quiont un déficit chronique en GSH (70-80%), afin d'étudier le lien entre une dérégulation rédoxet la schizophrénie. Nous avons évalué si ces souris présentent des altérationscomportementales analogues aux symptômes de la maladie, et des modificationsstructurelles, fonctionnelles et métaboliques au niveau du cerveau, ressemblant à celles despatients. De plus, nous avons soumis les souris à des stresses modérés durant la puberté,puis mesuré les réponses hormonales et comportementales. Les animaux présentent undéficit pré-attentionnel du traitement des informations moto-sensorielles, un déficit pourcertains apprentissages, une réponse accrue à l'amphétamine, mais leurs mémoires spatialeet de travail sont préservées. Ces atteintes comportementales sont analogues à certainsendophénotypes de la schizophrénie. De plus, ces changements comportementaux sontlargement expliqués par une perturbation morphologique et fonctionnelle de l'hippocampeventral (HV). Ainsi, nous avons observé un déficit sélectif des interneurones immunoréactifsà la parvalbumine et une désynchronisation neuronale dans l'HV. L'hippocampe dorsal,impliqué dans l'orientation spatiale, demeure en revanche intact. L'augmentationd'hormones de stress dans le sang des souris KO suite à un stress prépubertal soutien aussil'hypothèse d'une dysfonction de l'HV, connu pour moduler ce type de réponse. Des déficitsstructurels et fonctionnels dans l'hippocampe antérieur (ventral) ont d'ailleurs été rapportéschez des patients schizophrènes. Par de résonance magnétique, nous avons également suivile profil métabolique du le cortex antérieur au cours du développement postnatal des sourisKO. Ces mesures ont révélé des taux élevés de glutamine (Gln), glutamate (Glu), du ratioGln/Glu, et de N-acétyl-aspartate (NAA) durant la période prépubertale. Des altérationssimilaires sont décrites chez les patients durant la phase précoce. Nous avons donc révélédes anomalies phénotypiques chez les souris GCLM KO qui reflètent certainsendophénotypes de la schizophrénie. Nos résultats appuient donc le rôle d'une dérégulationrédox dans l'émergence de la maladie et le potentiel des souris KO comme modèle. De plus,cette étude met en évidence la puberté comme période particulièrement sensible à unedérégulation rédox, renforçant l'importance d'une intervention thérapeutique précoce. Dansce cadre, Gln, Gln/Glu, Glu and NAA seraient des biomarqueurs clés pour identifier de jeunesindividus à risque. De part son efficacité dans notre modèle, NAC pourrait être unesubstance de choix dans le traitement précoce des patients.

Second neoplasms after invasive and borderline ovarian cancer.

Excess risk of subsequent cancers has been documented in women diagnosed with ovarian cancer. We updated to 2006 data on second cancers in women diagnosed with invasive and borderline ovarian cancer in the Swiss canton of Vaud. Between 1974 and 2006, 304 borderline and 1530 invasive first ovarian tumours were abstracted from the Vaud Cancer Registry database and followed up till the end of 2006. Calculation of expected numbers of tumours in the cohorts was based on site-specific, age-specific and calendar-year-specific incidence rates. We computed the standardized incidence ratios (SIRs) of second cancers, and the corresponding 95% confidence intervals (CI). There was no change in the incidence of malignant cancers, but that of borderline tumours increased over more recent years. Overall, 110 second neoplasms were observed versus 49.7 expected after invasive ovarian cancer (SIR 2.21; 95% CI: 1.82-2.67). Significant excess risks were observed for cancers of the breast, corpus uteri and leukaemias. When synchronous cancers were excluded, the overall SIR for all sites declined to 1.05. Thirty-one second neoplasms were observed after borderline tumours compared with 21.1 expected (SIR=1.47; 95% CI: 1.00-2.09). SIRs were above unity for ovary, colorectum and uterus. After exclusion of synchronous neoplasms, SIR for all neoplasms declined to 1.09, and remained significant only for second ovarian cancers (SIR=4.93). The present record linkage cohort study shows an excess risk for selected synchronous neoplasms in women diagnosed with both borderline and invasive ovarian cancer, likely because of shared genetic and perhaps environmental factors.

Genetic diversity of Brazilian triticales evaluated with genomic wheat microsatellites

The objective of this work was to determine the genetic variability available for triticale (X Triticosecale Wittmack) crop improvement in Brazil. Forty-two wheat genomic microsatellites were used to estimate the molecular diversity of 54 genotypes, which constitute the base of one of the major triticale breeding programs in the country. Average heterozygosity was 0.06 and average and effective number of alleles per locus were 2.13 and 1.61, respectively, with average allelic frequency of 0.34. The set of genomic wheat microsatellites used clustered the genotypes into seven groups, even when the germplasm was originated primarily from only two triticale breeding programs, a fact reflected on the average polymorphic information content value estimated for the germplasm (0.36). The 71.42% transferability achieved for the tested microsatellites indicates the possibility of exploiting these transferable markers in further triticale genetic and breeding studies, even those mapped on the D genome of wheat, when analyzing hexaploid triticales.

No interactions between previously associated 2-hour glucose gene variants and physical activity or BMI on 2-hour glucose levels.

Gene-lifestyle interactions have been suggested to contribute to the development of type 2 diabetes. Glucose levels 2 h after a standard 75-g glucose challenge are used to diagnose diabetes and are associated with both genetic and lifestyle factors. However, whether these factors interact to determine 2-h glucose levels is unknown. We meta-analyzed single nucleotide polymorphism (SNP) × BMI and SNP × physical activity (PA) interaction regression models for five SNPs previously associated with 2-h glucose levels from up to 22 studies comprising 54,884 individuals without diabetes. PA levels were dichotomized, with individuals below the first quintile classified as inactive (20%) and the remainder as active (80%). BMI was considered a continuous trait. Inactive individuals had higher 2-h glucose levels than active individuals (β = 0.22 mmol/L [95% CI 0.13-0.31], P = 1.63 × 10(-6)). All SNPs were associated with 2-h glucose (β = 0.06-0.12 mmol/allele, P ≤ 1.53 × 10(-7)), but no significant interactions were found with PA (P > 0.18) or BMI (P ≥ 0.04). In this large study of gene-lifestyle interaction, we observed no interactions between genetic and lifestyle factors, both of which were associated with 2-h glucose. It is perhaps unlikely that top loci from genome-wide association studies will exhibit strong subgroup-specific effects, and may not, therefore, make the best candidates for the study of interactions.

Hyperuricaemia and gout: state of the art and future perspectives.

Major progress has been made in the past decade in understanding the pathogenesis and treatment of gout. These advances include identification of the genetic and environmental risk factors for gout, recognition that gout is an important risk factor for cardiovascular disease, elucidation of the pathways regulating the acute gout attack and the development of novel therapeutic agents to treat both the acute and chronic phases of the disease. This review summarises these advances and highlights the research agenda for the next decade.

Early glutathione deficit impairs parvalbumin expression in gaba interneurons and kainate-induced gamma oscillations

An increased oxidative stress and alteration of the antioxidant systems have been observed in schizophrenia. Glutathione (GSH), a major redox regulator, is decreased in patients' cerebrospinal fluid, prefrontal cortex in vivo and striatum post-mortem tissue. Most importantly, there is genetic and functional evidence for the implication of the gene of the glutamate cysteine ligase (GCL) catalytic subunit, the key GSH-synthesizing enzyme. We have developed animal models for a GSH deficit to study the consequences of such deficit on the brain development. A GSH deficit combined with elevated dopamine (DA) during development leads to reduced parvalbumin (PV) expression in a subclass of GABA interneurons in rat anterior cingulate cortex (ACC). Similar changes are observed in postmortem brain tissue of schizophrenic patients. GSH dysregulation increases vulnerability to oxidative stress, that in turn could lead to cortical circuit anomalies in the schizophrenic brain. In the present study, we use a GCL modulatory subunit (GCLM) knock-out (KO) mouse model that presents up to 80% decreased brain GSH levels. During postnatal development, a subgroup of animals from each genotype is exposed to elevated oxidative stress induced by treatment with the DA reuptake inhibitor GBR12909. Results reveal a significant genotype-specific delay International Congress on Schizophrenia Research 136 10. 10. Neuroanatomy, Animal Downloaded from http://schizophreniabulletin.oxfordjournals.org at Bibliotheque Cantonale et Universitaire on June 18, 2010 in cortical PV expression at postnatal day P10 in GCLM-KO mice, as compared to wild-type. This effect seems to be further exaggerated in animals treated with GBR12909 from P5 to P10. At P20, PV expression is no longer significantly reduced in GCLM-KO ACC without GBR but is reduced if GBR is applied from P10 to P20. However, our result show that GCLM-KO mice exhibit increased oxidative stress, cortical altered myelin development as shown by MBP marker, and more specifically impairment of the peri-neuronal net known to modulate PV connectivity. In addition, we also observe a reduced PV expression in the ventro-temporal hippocampus of adult GCLM-KO mice, suggesting that anomalies of the PV interneurons prevail at least in some brain regions throughout the adulthood. Interestingly, the power of kainate-induced gamma oscillations, known to be dependent on proper activation of PV interneuron's, is also lower in hippocampal slices of adult GCLM KO mice. These results suggest that the PV positive GABA interneurons is particularly vulnerable to increased oxidative stress