Functional Brain Network Characterization and Adaptivity during Task Practice in Healthy Volunteers and People with Schizophrenia1

Cognitive remediation involves task practice and may improve deficits in people suffering from schizophrenia, but little is known about underlying neurophysiological mechanisms. In people with schizophrenia and controls, we used magnetoencephalography (MEG) to examine accuracy and practice-related changes in parameters indexing neural network structure and activity, to determine whether these might be useful assays of the efficacy of cognitive remediation. Two MEG recordings were acquired during performance of a tone discrimination task used to improve the acuity of auditory processing, before and after ∼2.5 h of task practice. Accuracy before practice was negatively correlated with beta-band cost efficiency, a graph theoretical measure of network organization. Synthetic aperture magnetometry was used to localize brain oscillations with high spatial accuracy; results demonstrated sound and sensorimotor modulations of the beta band in temporo-parietal regions and the sensorimotor cortex respectively. High-gamma activity also correlated with sensorimotor processing during the task, with activation of auditory regions following sound stimulation, and activation of the left sensorimotor cortex preceding the button press. High-gamma power in the left frontal cortex was also found to correlate with accuracy. Following practice, sound-induced broad-band power in the left angular gyri increased. Accuracy improved and was found to correlate with increased mutual information (MI) between sensors in temporal–parietal regions in the beta band but not global cost efficiency. Based on these results, we conclude that hours of task practice can induce meso-scale changes such as increased power in relevant brain regions as well as changes in MI that correlate with improved accuracy

Dysregulated protocadherin-pathway activity as an intrinsic defect in induced pluripotent stem cell-derived cortical interneurons from subjects with schizophrenia.

We generated cortical interneurons (cINs) from induced pluripotent stem cells derived from 14 healthy controls and 14 subjects with schizophrenia. Both healthy control cINs and schizophrenia cINs were authentic, fired spontaneously, received functional excitatory inputs from host neurons, and induced GABA-mediated inhibition in host neurons in vivo. However, schizophrenia cINs had dysregulated expression of protocadherin genes, which lie within documented schizophrenia loci. Mice lacking protocadherin-α showed defective arborization and synaptic density of prefrontal cortex cINs and behavioral abnormalities. Schizophrenia cINs similarly showed defects in synaptic density and arborization that were reversed by inhibitors of protein kinase C, a downstream kinase in the protocadherin pathway. These findings reveal an intrinsic abnormality in schizophrenia cINs in the absence of any circuit-driven pathology. They also demonstrate the utility of homogenous and functional populations of a relevant neuronal subtype for probing pathogenesis mechanisms during development

Variation in dopamine D2 and serotonin 5-HT2A receptor genes is associated with working memory processing and response to treatment with antipsychotics

Dopamine D2 and serotonin 5-HT2A receptors contribute to modulate prefrontal cortical physiology and response to treatment with antipsychotics in schizophrenia. Similarly, functional variation in the genes encoding these receptors is also associated with these phenotypes. In particular, the DRD2 rs1076560 T allele predicts a lower ratio of expression of D2 short/long isoforms, suboptimal working memory processing, and better response to antipsychotic treatment compared with the G allele. Furthermore, the HTR2A T allele is associated with lower 5-HT2A expression, impaired working memory processing, and poorer response to antipsychotics compared with the C allele. Here, we investigated in healthy subjects whether these functional polymorphisms have a combined effect on prefrontal cortical physiology and related cognitive behavior linked to schizophrenia as well as on response to treatment with secondgeneration antipsychotics in patients with schizophrenia. In a total sample of 620 healthy subjects, we found that subjects with the rs1076560 T and rs6314 T alleles have greater fMRI prefrontal activity during working memory. Similar results were obtained within the attentional domain. Also, the concomitant presence of the rs1076560 T/rs6314 T alleles also predicted lower behavioral accuracy during working memory. Moreover, we found that rs1076560 T carrier/rs6314 CC individuals had better responses to antipsychotic treatment in two independent samples of patients with schizophrenia (n¼63 and n¼54, respectively), consistent with the previously reported separate effects of these genotypes. These results indicate that DRD2 and HTR2A genetic variants together modulate physiological prefrontal efficiency during working memory and also modulate the response to antipsychotics. Therefore, these results suggest that further exploration is needed to better understand the clinical consequences of these genotype–phenotype relationships

Proteolytic Activity of Oenococcus oeni Enables the Increase in Antioxidant and Antihypertensive Activities from Wine

Oenococcus oeni is a lactic acid bacterium involved in winemaking where it generally carries out the malolactic fermentation converting the wine's malic acid into lactic acid. In this work were used the strain m of Oenococcus oeni. The culture was inoculated at 108 Log CFU/mL in a synthetic wine medium (SW) supplemented with a fraction of high molecular weight constituted by proteins and polypeptides (FPP) obtained from Cabernet Sauvignon and Syrah wines from Colalao del Valle, Tucumán, Argentine. In presence of FPP, O. oeni maintains viability after 48 h incubation time and release an extracellular proteolytic activity. Therefore, a release peptides of 1.247 and 1.373 mg N/L at 48 h of incubation time was detected in SW supplemented with FPP from Cabernet Sauvignon and Syrah wines respectively. Concomitantly with the maximum peptide release, the “in vitro” biological activities were increased. The released peptides from Cabernet Sauvignon wine enables the increase in the ferric reducing antioxidant power (FRAP) capacity, the scavenging activity of 2,2-diphenyl-1-picrylhydrazyl radical (DPPH), and the inhibition of angiotensin I-converting enzyme (ACEI activity) in 392.8 µmol FeSO4/L, 9.7% and 63.9%, respectively. In presence of FPP of Syrah wine, the released peptides increases in 156.5 µmol FeSO4/L, 5.5% and 13.8% the FRAP, DPPH and ACEI activities, respectively. The utilization of Oenococcus oeni m to carry out the malolactic fermentation would contribute to enhance the beneficial biological activities of the final product and provide an additional value to regional wines.Fil: Apud, Gisselle Raquel. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tucumán; ArgentinaFil: Stivala, Maria Gilda. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tucumán; ArgentinaFil: Aredes Fernández, Pedro Adrián. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tucumán; ArgentinaFil: Rodriguez Vaquero, Maria Jose. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tucumán; Argentin

Common and Differential Pathophysiological Features Accompany Comparable Cognitive Impairments in Medication-Free Patients with Schizophrenia and in Healthy Aging Subjects

International audienc

Increase in antioxidant and antihypertensive peptides from Argentinean wines by Oenococcus oeni

Cells from an exponential Oenococcus oeni m1 culture in a grape juice medium were inoculated into a synthetic wine medium (SW) supplemented with a protein and polypeptide fraction (PPF) of high molecular weight (higher than 12,400 Da) obtained from four varietals of Cafayate Argentinean wines. O. oeni maintains viability after 48 h incubation time and enables the increase in extracellular proteolytic activity and the release of low molecular weight peptides by 1.067, 0.397, 0.915 and 0.705 mg N/L in the respective SW supplemented with PPF from Cabernet Sauvignon, Malbec, Tannat and Torrontés wine varietals. After 48 h incubation time, concomitantly with peptide release, an increase in antioxidant and antihypertensive activities was detected in all studied media. The highest increase was detected in the presence of PPF from Cabernet and Tannat wine varietals. Maximum increase in antioxidant activity (366.1 μmol FeSO4/L in the case of ferric reducing antioxidant power and 8.9% in 2,2-diphenyl-1-picrylhydrazyl radical scavenging) was produced by the peptides released from PPF of Cabernet Sauvignon wine. The peptides released from PPF Tannat wine varietal caused the highest increase in antihypertensive activity (56.2% in angiotensin I-converting enzyme inhibitory activity). Oenococcus oeni m1 would provide additional benefits to wine such as an increase in bioactive peptides with multifunctional beneficial activities.Fil: Aredes Fernández, Pedro Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tucumán. Centro de Referencia Para Lactobacilos (i); Argentina; Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia; Argentina;Fil: Apud, Gisselle Raquel. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia; Argentina;Fil: Stivala, Maria Gilda. Universidad Nacional de Tucuman. Facultad de Bioquimica, Quimica y Farmacia. Instituto de Quimica Organica. Catedra de Quimica Organica Ii; Argentina;Fil: Rodriguez Vaquero, Maria Jose. Universidad Nacional de Tucuman. Facultad de Bioquimica, Quimica y Farmacia. Instituto de Microbiologia;Fil: Rollan, Graciela Celestina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tucumán. Centro de Referencia Para Lactobacilos (i); Argentina

Functional Analysis of Genetic Variation in Catechol-O-Methyltransferase (COMT): Effects on mRNA, Protein, and Enzyme Activity in Postmortem Human Brain

Catechol-O-methyltransferase (COMT) is a key enzyme in the elimination of dopamine in the prefrontal cortex of the human brain. Genetic variation in the COMT gene (MIM 116790) has been associated with altered prefrontal cortex function and higher risk for schizophrenia, but the specific alleles and their functional implications have been controversial. We analyzed the effects of several single-nucleotide polymorphisms (SNPs) within COMT on mRNA expression levels (using reverse-transcriptase polymerase chain reaction analysis), protein levels (using Western blot analysis), and enzyme activity (using catechol methylation) in a large sample (n = 108) of postmortem human prefrontal cortex tissue, which predominantly expresses the -membrane-bound isoform. A common coding SNP, Val158Met (rs4680), significantly affected protein abundance and enzyme activity but not mRNA expression levels, suggesting that differences in protein integrity account for the difference in enzyme activity between alleles. A SNP in intron 1 (rs737865) and a SNP in the 3′ flanking region (rs165599)—both of which have been reported to contribute to allelic expression differences and to be associated with schizophrenia as part of a haplotype with Val—had no effect on mRNA expression levels, protein immunoreactivity, or enzyme activity. In lymphocytes from 47 subjects, we confirmed a similar effect on enzyme activity in samples with the Val/Met genotype but no effect in samples with the intron 1 or 3′ SNPs. Separate analyses revealed that the subject's sex, as well as the presence of a SNP in the P2 promoter region (rs2097603), had small effects on COMT enzyme activity. Using site-directed mutagenesis of mouse COMT cDNA, followed by in vitro translation, we found that the conversion of Leu at the homologous position into Met or Val progressively and significantly diminished enzyme activity. Thus, although we cannot exclude a more complex genetic basis for functional effects of COMT, Val is a predominant factor that determines higher COMT activity in the prefrontal cortex, which presumably leads to lower synaptic dopamine levels and relatively deleterious prefrontal function