carbocyanines and Schizophrenia

Topics: Benzimidazoles; Carbocyanines; Cell Culture Techniques; Fibroblasts; Fluorescent Dyes; Humans; Image Processing, Computer-Assisted; Membrane Potential, Mitochondrial; Microscopy, Confocal; Mitochondria; Proof of Concept Study; Schizophrenia; Xanthenes

Mitochondria have been suggested to be involved in the pathology of bipolar disorder (BD) and schizophrenia. However, the mechanism underlying mitochondrial dysfunction is unclear. Mitochondrial network dynamics, which reflects cellular metabolic state, is important for embryonic development, synapse formation, and neurodegeneration. This study aimed to investigate mitochondrial network dynamics and its plausible association with abnormal cellular oxygen consumption in schizophrenia.. Viable Epstein-Barr virus (EBV)-transformed lymphocytes (lymphoblastoids) from DSM-IV diagnosed patients with schizophrenia (n = 17), BD (n = 15), and healthy control subjects (n = 15) were assessed for mitochondrial respiration, mitochondrial dynamics, and relevant protein levels by oxygraph, confocal microscopy, and immunoblotting, respectively.. Respiration of schizophrenia-derived lymphoblastoids was significantly lower compared with control subjects, and was twice as sensitive to dopamine (DA)-induced inhibition. Unlike DA, haloperidol inhibited complex I-driven respiration to a similar extent in both schizophrenia and the control cells. Both drugs interact with complex I but at different sites. At the site of DA interaction, we found alterations in protein levels of three subunits of complex I in schizophrenia. In addition, we observed structural and connectivity perturbations in the mitochondrial network, associated with alterations in the profusion protein OPA1, which was similarly reduced in schizophrenia prefrontal cortex specimens. None of these alterations were observed in the BD cells, which were similar to control cells.. We show impaired mitochondrial network dynamics associated with reduced cellular respiration and complex I abnormalities in schizophrenia but not in BD. If these findings represent disease-specific alterations, they may become an endophenotype biomarker for schizophrenia.

Topics: Adult; Analysis of Variance; Animals; Antipsychotic Agents; Benzimidazoles; Carbocyanines; Cell Line, Transformed; Cell Respiration; Electron Transport Complex I; Female; GTP Phosphohydrolases; Herpesvirus 4, Human; Humans; Lymphocytes; Male; Membrane Potential, Mitochondrial; Membrane Transport Proteins; Middle Aged; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Proteins; Oxygen Consumption; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Schizophrenia; Ultrasonography; Young Adult

Two-dimensional difference gel electrophoresis (DIGE) is a tool for measuring changes in protein expression between samples involving pre-electrophoretic labeling ith cyanine dyes. In multi-gel experiments, univariate statistical tests have been used to identify differential expression between sample types by looking for significant changes in spot volume. Multivariate statistical tests, which look for correlated changes between sample types, provide an alternate approach for identifying spots with differential expression. Partial least squares-discriminant analysis (PLS-DA), a multivariate statistical approach, was combined with an iterative threshold process to identify which protein spots had the greatest contribution to the model, and compared to univariate test for three datasets. This included one dataset where no biological difference was expected. The novel multivariate approach, detailed here, represents a method to complement the univariate approach in identification of differentially expressed protein spots. This new approach has the advantages of reduced risk of false-positives and the identification of spots that are significantly altered in terms of correlated expression rather than absolute expression values.

Topics: Analysis of Variance; Animals; Bacterial Proteins; Brain Chemistry; Carbocyanines; Circadian Rhythm; Coloring Agents; Discriminant Analysis; Electrophoresis, Gel, Two-Dimensional; False Positive Reactions; Humans; Least-Squares Analysis; Liver; Mice; Pectobacterium carotovorum; Proteomics; Schizophrenia; Software