Abstract Autism spectrum disorder (ASD) is a heterogeneous disorder characterized by impaired social communication and restricted repetitive behaviors, however the biological mechanisms remain unclear. Although trace elements play essential roles in the living body, it is unclear how alterations of trace elements in ASD are involved in pathogenesis. Here we analyzed the plasma metallome and identified the alterations of 11 elements in individuals with ASD. The copper decrease was negatively correlated with ASD symptom scores. A copper-deficient mouse model reflecting the condition showed ASD-like behaviors and impaired oligodendrocyte development. In copper-deficient mice, mechanistic target of rapamycin (mTOR) signaling was reduced, and its activation by agonist improved social impairment and oligodendrocyte developmental defects. Supporting these results, white matter volumes were negatively correlated with social symptoms in individuals with ASD. Our results demonstrate that copper-deficiency contributes to ASD by causing oligodendrocytes impairment via mTOR signaling. Our findings indicate that the effects of copper-deficiency and mTOR imbalance are relevant to the pathogenesis of ASD and are potential therapeutic targets.
Separate lines of evidence have demonstrated the involvement of N-methyl-D-aspartate (NMDA) receptor and oligodendrocyte dysfunctions in schizophrenia. Here, we have carried out shotgun mass spectrometry proteome analysis of oligodendrocytes treated with the NMDA receptor antagonist MK-801 to gain potential insights into these effects at the molecular level. The MK-801 treatment led to alterations in the levels of 68 proteins, which are associated with seven distinct biological processes. Most of these proteins are involved in energy metabolism and many have been found to be dysregulated in previous proteomic studies of post-mortem brain tissues from schizophrenia patients. Finally, addition of the antipsychotic clozapine to MK-801-treated oligodendrocyte cultures resulted in changes in the levels of 45 proteins and treatment with clozapine alone altered 122 proteins and many of these showed opposite changes to the MK-801 effects. Therefore, these proteins and the associated energy metabolism pathways should be explored as potential biomarkers of antipsychotic efficacy. In conclusion, MK-801 treatment of oligodendrocytes may provide a useful model for testing the efficacy of novel treatment approaches.
An accessory spleen is found in 10-30% of necropsies, but seldom gives rise to symptoms and very rarely involves torsion. We treated a patient with such torsion. A 23-year-old man was admitted due to intermittent abdominal pain and fever. Laboratory findings showed leukocytosis. Abdominal ultrasonography, computed tomography, and magnetic resonance imaging revealed a solid tumor in the left upper abdominal quadrant. Preoperative diagnosis was an abdominal tumor. Explorative laparotomy showed a solid tumor in the greater omentum, 8.0×7.2×4.8cm. It had a long twisted pedicle connected to the gastroepiploic artery and vein. Macroscopically, the tumor was homogenous, dark red, and solid tumor. Microscopically, it contained splenic tissue with necrosis and fibrosis. The final diagnosis was torsion of an accessory spleen with infarction, causing abdominal pain. It should be considered in the differential diagnosis of intraabdominal mass with abdominal pain in adolescents.
Background Obstetric complications have been regarded as a risk factor for schizophrenia later in life. One of the mechanisms underlying the association is postulated to be a hypoxic process in the brain in the offspring around the time of birth. Hippocampus is one of the brain regions implicated in the late-onset dopaminergic dysfunction associated with hypoxic obstetric complications. Methodology/Principal Findings We used an animal model of perinatal asphyxia, in which rat pups were exposed to 15 min of intrauterine anoxia during Cesarean section birth. At 6 and 12 weeks after birth, the behavior of the pups was assessed using a methamphetamine-induced locomotion test. In addition, the histopathology of the hippocampus was examined by means of stereology. At 6 weeks, there was no change in the methamphetamine-induced locomotion. However, at 12 weeks of age, we found an elevation in methamphetamine-induced locomotor activity, which was associated with an increase of dopamine release in the nucleus accumbens. At the same age, we also found a reduction of the dentate granule cells of the hippocampus. Conclusions/Significance These results suggest that the dopaminergic dysregulation after perinatal asphyxia is associated with a reduction in hippocampal dentate granule cells, and this may partly contribute to the pathogenesis of schizophrenia.
Mitochondria are essential for brain function, and accumulating evidence from postmortem brain studies, neuroimaging, and basic research indicates mitochondrial impairments in patients with psychiatric disorders. Restoring mitochondrial function therefore represents a promising therapeutic strategy for these conditions. Mitochondrial transplantation, an innovative approach that uses functional mitochondria to repair damaged cells, has demonstrated efficacy through various delivery methods in cell, animal, and animal disease models. This review explores the critical link between mitochondria and psychiatric disorders and provides an overview of mitochondrial transplantation as a therapeutic intervention. It highlights recent advances in mitochondrial transplantation in animal models of psychiatric disorders, focusing on delivery methods, the timing of administration, and the integration of exogenous mitochondria into brain cells. The potential therapeutic effects and the mechanisms that underlie these effects are discussed. Additionally, this review evaluates the clinical relevance, challenges, and future strategies for the application of mitochondrial transplantation in the treatment of psychiatric disorders.
Motoneurons are particularly sensitive to mutations in mitofusin-2 (MFN2) that cause the neurological disorder Charcot-Marie-Tooth disease type 2A (CMT2A). MFN2 is a mitochondrial outer membrane protein that, together with its homologue MFN1, fuses mitochondria in most tissues. In this issue of the JCI, Zhou and colleagues show that increasing MFN1 expression in neurons can curtail neurological defects in a CMT2A mouse model. These results show that the ratio of MFN1 to MFN2 can explain the tissue specificity of CMT2A and indicate that augmentation of MFN1 in the nervous system has potential as a possible therapeutic strategy for CMT2A.
