FOXP2 expression and gray matter density in the male brains of patients with schizophrenia.

Common genetic variants of FOXP2 may contribute to schizophrenia vulnerability, but controversial results have been reported for this proposal. Here we evaluated the potential impact of the common FOXP2 rs2396753 polymorphism in schizophrenia. It was previously reported to be part of a risk haplotype for this disease and to have significant effects on gray matter concentration in the patients. We undertook the first examination into whether rs2396753 affects the brain expression of FOXP2 and a replication study of earlier neuroimaging findings of the influence of this genetic variant on brain structure. FOXP2 expression levels were measured in postmortem prefrontal cortex samples of 84 male subjects (48 patients and 36 controls) from the CIBERSAM Brain and the Stanley Foundation Array Collections. High-resolution anatomical magnetic resonance imaging was performed on 79 male subjects (61 patients, 18 controls) using optimized voxel-based morphometry. We found differences in FOXP2 expression and brain morphometry depending on the rs2396753, relating low FOXP2 mRNA levels with reduction of gray matter density. We detected an interaction between rs2396753 and the clinical groups, showing that heterozygous patients for this polymorphism have gray matter density decrease and low FOXP2 expression comparing with the heterozygous controls. This study shows the importance of independent replication of neuroimaging genetic studies of FOXP2 as a candidate gene in schizophrenia. Furthermore, our results suggest that the FOXP2 rs2396753 affects mRNA levels, thus providing new knowledge about its significance as a potential susceptibility polymorphism in schizophrenia.

Time dependent expression of the blood biomarkers EIF2D and TOX in patients with schizophrenia.

BACKGROUND: During last years, there has been an intensive search for blood biomarkers in schizophrenia to assist in diagnosis, prognosis and clinical management of the disease. METHODS: In this study, we first conducted a weighted gene coexpression network analysis to address differentially expressed genes in peripheral blood from patients with chronic schizophrenia (n = 30) and healthy controls (n = 15). The discriminating performance of the candidate genes was further tested in an independent cohort of patients with first-episode schizophrenia (n = 124) and healthy controls (n = 54), and in postmortem brain samples (cingulate and prefrontal cortices) from patients with schizophrenia (n = 34) and healthy controls (n = 35). RESULTS: The expression of the Eukaryotic Translation Initiation Factor 2D (EIF2D) gene, which is involved in protein synthesis regulation, was increased in the chronic patients of schizophrenia. On the contrary, the expression of the Thymocyte Selection-Associated High Mobility Group Box (TOX) gene, involved in immune function, was reduced. EIF2D expression was also altered in first-episode schizophrenia patients, but showing reduced levels. Any of the postmortem brain areas studied did not show differences of expression of both genes. CONCLUSIONS: EIF2D and TOX are putative blood markers of chronic patients of schizophrenia, which expression change from the onset to the chronic disease, unraveling new biological pathways that can be used for the development of new intervention strategies in the diagnosis and prognosis of schizophrenia disease.

Drosophila melanogaster Models of Metal-Related Human Diseases and Metal Toxicity.

Iron, copper and zinc are transition metals essential for life because they are required in a multitude of biological processes. Organisms have evolved to acquire metals from nutrition and to maintain adequate levels of each metal to avoid damaging effects associated with its deficiency, excess or misplacement. Interestingly, the main components of metal homeostatic pathways are conserved, with many orthologues of the human metal-related genes having been identified and characterized in Drosophila melanogaster. Drosophila has gained appreciation as a useful model for studying human diseases, including those caused by mutations in pathways controlling cellular metal homeostasis. Flies have many advantages in the laboratory, such as a short life cycle, easy handling and inexpensive maintenance. Furthermore, they can be raised in a large number. In addition, flies are greatly appreciated because they offer a considerable number of genetic tools to address some of the unresolved questions concerning disease pathology, which in turn could contribute to our understanding of the metal metabolism and homeostasis. This review recapitulates the metabolism of the principal transition metals, namely iron, zinc and copper, in Drosophila and the utility of this organism as an experimental model to explore the role of metal dyshomeostasis in different human diseases. Finally, a summary of the contribution of Drosophila as a model for testing metal toxicity is provided.

Early Social Isolation Stress and Perinatal NMDA Receptor Antagonist Treatment Induce Changes in the Structure and Neurochemistry of Inhibitory Neurons of the Adult Amygdala and Prefrontal Cortex.

The exposure to aversive experiences during early life influences brain development and leads to altered behavior. Moreover, the combination of these experiences with subtle alterations in neurodevelopment may contribute to the emergence of psychiatric disorders, such as schizophrenia. Recent hypotheses suggest that imbalances between excitatory and inhibitory (E/I) neurotransmission, especially in the prefrontal cortex and the amygdala, may underlie their etiopathology. In order to understand better the neurobiological bases of these alterations, we studied the impact of altered neurodevelopment and chronic early-life stress on these two brain regions. Transgenic mice displaying fluorescent excitatory and inhibitory neurons, received a single injection of MK801 (NMDAR antagonist) or vehicle solution at postnatal day 7 and/or were socially isolated from the age of weaning until adulthood (3 months old). We found that anxiety-related behavior, brain volume, neuronal structure, and the expression of molecules related to plasticity and E/I neurotransmission in adult mice were importantly affected by early-life stress. Interestingly, many of these effects were potentiated when the stress paradigm was applied to mice perinatally injected with MK801 ("double-hit" model). These results clearly show the impact of early-life stress on the adult brain, especially on the structure and plasticity of inhibitory networks, and highlight the double-hit model as a valuable tool to study the contribution of early-life stress in the emergence of neurodevelopmental psychiatric disorders, such as schizophrenia.

Semaphorin and plexin gene expression is altered in the prefrontal cortex of schizophrenia patients with and without auditory hallucinations.

Auditory hallucinations (AH) are clinical hallmarks of schizophrenia, however little is known about molecular genetics of these symptoms. In this study, gene expression profiling of postmortem brain samples from prefrontal cortex of schizophrenic patients without AH (SNA), patients with AH (SA) and control subjects were compared. Genome-wide expression analysis was conducted using samples of three individuals of each group and the Affymetrix GeneChip Human-Gene 1.0 ST-Array. This analysis identified the Axon Guidance pathway as one of the most differentially expressed network among SNA, SA and CNT. To confirm the transcriptome results, mRNA level quantification of seventeen genes involved in this pathway was performed in a larger sample. PLXNB1, SEMA3A, SEMA4D and SEM6C were upregulated in SNA or SA patients compared to controls. PLXNA1 and SEMA3D showed down-regulation in their expression in the patient's samples, but differences remained statistically significant between the SNA patients and controls. Differences between SNA and SA were found in PLXNB1 expression which is decreased in SA patients. This study strengthens the contribution of brain plasticity in pathophysiology of schizophrenia and shows that non-hallucinatory patients present more alterations in frontal regions than patients with hallucinations concerning neural plasticity.