Evaluation of expression profile in autism spectrum disorder (ASD) patients is an important approach to understand possible similar functional consequences that may underlie disease pathophysiology regardless of its genetic heterogeneity. Induced pluripotent stem cell (iPSC)-derived neuronal models have been useful to explore this question, but larger cohorts and different ASD endophenotypes still need to be investigated. Moreover, whether changes seen in this in vitro model reflect previous findings in ASD postmortem brains and how consistent they are across the studies remain underexplored questions. We examined the transcriptome of iPSC-derived neuronal cells from a normocephalic ASD cohort composed mostly of high-functioning individuals and from non-ASD individuals. ASD patients presented expression dysregulation of a module of co-expressed genes involved in protein synthesis in neuronal progenitor cells (NPC), and a module of genes related to synapse/neurotransmission and a module related to translation in neurons. Proteomic analysis in NPC revealed potential molecular links between the modules dysregulated in NPC and in neurons. Remarkably, the comparison of our results to a series of transcriptome studies revealed that the module related to synapse has been consistently found as upregulated in iPSC-derived neurons-which has an expression profile more closely related to fetal brain-while downregulated in postmortem brain tissue, indicating a reliable association of this network to the disease and suggesting that its dysregulation might occur in different directions across development in ASD individuals. Therefore, the expression pattern of this network might be used as biomarker for ASD and should be experimentally explored as a therapeutic target.

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Schizophrenia is a chronic, severe and disabling psychiatric disorder, whose treatment is based on psychosocial interventions and the use of antipsychotic drugs. While the effects of these drugs are well elucidated in neuronal cells, they are still not so clear in oligodendrocytes, which play a vital role in schizophrenia. Thus, we aimed to characterize biochemical profiles by proteomic analyses of human oligodendrocytes (MO3.13) which were matured using a protocol we developed and treated with either haloperidol (a typical antipsychotic), clozapine (an atypical antipsychotic) or a clozapine + d-serine co-treatment, which has emerged lately as an alternative type of treatment. this was accomplished by employing shotgun proteomics, using nanoeSi-Lc-MS/MS labelfree quantitation. Proteomic analysis revealed biochemical pathways commonly affected by all tested antipsychotics were mainly associated to ubiquitination, proteasome degradation, lipid metabolism and DNA damage repair. Clozapine and haloperidol treatments also affected proteins involved with the actin cytoskeleton and with EIF2 signaling. In turn, metabolic processes, especially the metabolism of nitrogenous compounds, were a predominant target of modulation of clozapine + d-serine treatment. in this context, we seek to contribute to the understanding of the biochemical and molecular mechanisms involved in the action of antipsychotics on oligodendrocytes, along with their possible implications in schizophrenia. Abbreviations ACC Anterior cingulate cortex ACN Acetonitrile ACTB Beta-actin CNPase 2′,3′-Cyclic-nucleotide-3-phosphodiesterase COPS8 COP9 signalosome complex subunit 8 DIA Data-independent acquisition DLPFC Dorsolateral prefrontal cortex DMEM Dulbecco's modified eagle medium DTT Dithiothreitol eIF2 Eukaryotic initiation factor-2

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Interest in the modulation of endocannabinoid signaling has increased since the discovery of receptors for compounds of Cannabis sativa. Endocannabinoids are crucial neuromodulators of many brain functions and changes in the ligands and their receptors have been associated with psychiatric disorders, such as schizophrenia. Genetic, neuroimaging, and behavioral studies have reinforced the role of endocannabinoids in the pathobiology of schizophrenia. However, molecular pathways and biological processes involved in cannabinoid effects are not totally understood. Additionally, the endocannabinoid signaling network with other non-cannabinoid targets, and the effects of phytocannabinoids increase the complexity to understand their role in schizophrenia and homeostasis conditions. Thus, proteomic studies can provide evidence about the involvement of cannabinoid receptors, as well as the metabolic and synthetic enzymes of the endocannabinoids in these disorders. Additionally, quantification of endocannabinoids in the blood serum or cerebrospinal fluid can be a useful approach to identify new biomarkers in schizophrenia, and lipidomic techniques can be used to quantify these compounds. Herein, the authors review proteomic and lipidomic studies that have been used for analysis of the endocannabinoid system in healthy and schizophrenia function. The findings may contribute to understand the involvement of endocannabinoids in the brain and in the neurobiological basis of schizophrenia.

BackgroundPreclinical and clinical studies have suggested the involvement of the endocannabinoid system in schizophrenia pathobiology. In addition, in vitro studies have shown the molecular pathways and biological processes associated with cannabinoids’ effects in some cell types, such as glial cell cultures. Thus, the effects of cannabinoid drugs on these cells may contribute to our knowledge about the pathobiology of schizophrenia. Specifically, oligodendrocytes are associated with white matter deficits in schizophrenia. The modulation of their function, survival, and differentiation can result in new approaches to treat schizophrenia’s white matter-associated deficits. Here we have investigated the effects of cannabidiol (CBD) on a human oligodendrocyte culture (MO3.13). In another experiment, we pretreated the MO3.13 with MK801, an in vitro model of study schizophrenia proposed by our group, in terms of protein expression.MethodsMO3.13 oligodendrocytes were treated with CBD (1µM), or MK801 (50 µM) followed by CBD (1 µM). After 8 hours, proteins were extracted from these cells, digested, and processed in a state-of-the-art LC-MS/MS system. Quantitative proteomics approaches were then employed in a label-free fashion. Differentially expressed proteins were analyzed using systems biology in silico tools.ResultsAnalyses identified that several proteins were up- or down-regulated in response to CBD treatment. These proteins were analyzed in terms of biological processes, pathways, and functions. CBD affected the expression of 136 proteins. Some proteins such as the transient receptor potential channel, microtubule-associated proteins, Rho GTPase activating proteins (21 and 23), and the calcium channel, voltage-dependent T type alpha 1H subunit, among others possibly involved in myelination process, were increased by CBD. Additionally, the MK801-treatment decreased proteins of cytoskeleton, microtubule and RHO GTPases activate KTN1. MK801 also increased proteins involved in glycolysis and eukaryotic translation initiation and CBD attenuated these changes.DiscussionStudies have shown the effects of CBD on the treatment of schizophrenia; but the mechanisms involved in its antipsychotic properties are not fully understood. Herein, we observed that CBD modulated the expression of proteins that can be implicated in schizophrenia pathobiology. For instance, MAPs functions are related to cytoskeleton organization, differentiation, and migration of oligodendrocytes. Studies have shown a decrease of MAPs in schizophrenia patients; thus, increasing MAP2 and MAP4 by CBD may be an interesting mechanism to treat and prevent cytoskeleton impairments in oligodendrocytes and neurons in schizophrenia. Moreover, CBD increased the voltage gated channel that is involved in cannabinoid retrograde signaling and glutamate and GABAergic neurotransmission. CACNA1H modulates Ca2+ levels and the synaptic vesicle cycle. To note, we also found effects of CBD on pathways and biological processes involved with schizophrenia pathobiology,...