RESUMO
Although the link of white matter to pathophysiology of schizophrenia is documented, loss of myelin is not detected in patients at the early stages of the disease, suggesting that pathological evolution of schizophrenia may occur before significant myelin loss. Disrupted-in-schizophrenia-1 (DISC1) protein is highly expressed in oligodendrocyte precursor cells (OPCs) and regulates their maturation. Recently, DISC1-Δ3, a major DISC1 variant that lacks exon 3, has been identified in schizophrenia patients, although its pathological significance remains unknown. In this study, we detected in schizophrenia patients a previously unidentified pathological phenotype of OPCs exhibiting excessive branching. We replicated this phenotype by generating a mouse strain expressing DISC1-Δ3 gene in OPCs. We further demonstrated that pathological OPCs, rather than myelin defects, drive the onset of schizophrenic phenotype by hyperactivating OPCs' Wnt/ß-catenin pathway, which consequently upregulates Wnt Inhibitory Factor 1 (Wif1), leading to the aberrant synaptic formation and neuronal activity. Suppressing Wif1 in OPCs rescues synaptic loss and behavioral disorders in DISC1-Δ3 mice. Our findings reveal the pathogenetic role of OPC-specific DISC1-Δ3 variant in the onset of schizophrenia and highlight the therapeutic potential of Wif1 as an alternative target for the treatment of this disease.
Assuntos
Células Precursoras de Oligodendrócitos , Esquizofrenia , Animais , Humanos , Camundongos , Encéfalo/metabolismo , Encéfalo/patologia , Bainha de Mielina/metabolismo , Proteínas do Tecido Nervoso/genética , Células Precursoras de Oligodendrócitos/metabolismo , Células Precursoras de Oligodendrócitos/patologia , Oligodendroglia/metabolismo , Esquizofrenia/metabolismo , Esquizofrenia/patologia , Modelos Animais de DoençasRESUMO
Oligodendroglial lineage cells go through a series of morphological changes before myelination. Prior to myelination, cell processes and membrane structures enlarge by approximately 7,000 times, which is required to support axonal wrapping and myelin segment formation. Failure of these processes leads to maldevelopment and impaired myelination. Quetiapine, an atypical antipsychotic drug, was proved to promote oligodendroglial differentiation and (re)myelination, pending detailed effects and regulatory mechanism. In this study, we showed that quetiapine promotes morphological maturation of oligodendroglial lineage cells and myelin segment formation, and a short-term quetiapine treatment is sufficient to induce these changes. To uncover the underlying mechanism, we examined the effect of quetiapine on the Oligodendrocyte transcription factor 1 (Olig1). We found that quetiapine upregulates Olig1 expression level and promotes nuclear Olig1 translocation to the cytosol, where it functions not as a transcription modulator, but in a way that highly correlates with oligodendrocyte morphological transformation. In addition, quetiapine treatment reverses the negative regulatory effect of the Olig1-regulated G protein-coupled receptor 17 (GPR17) on oligodendroglial morphological maturation. Our results demonstrate that quetiapine enhances oligodendroglial differentiation and myelination by promoting cell morphological transformation. This would shed light on the orchestration of oligodendroglia developmental mechanisms, and provides new targets for further therapeutic research.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos , Oligodendroglia , Axônios/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Diferenciação Celular/fisiologia , Bainha de Mielina/metabolismo , Oligodendroglia/metabolismo , Fumarato de Quetiapina/metabolismo , Fumarato de Quetiapina/farmacologiaRESUMO
As the most abundant gap junction protein in the central nervous system (CNS), astrocytic connexin 43 (Cx43) maintains astrocyte network homeostasis, affects oligodendroglial development and participates in CNS pathologies as well as injury progression. However, its role in remyelination is not yet fully understood. To address this issue, we used astrocyte-specific Cx43 conditional knockout (Cx43 cKO) mice generated through the use of a hGFAP-cre promoter, in combination with mice carrying a floxed Cx43 allele that were subjected to lysolecithin so as to induce demyelination. We found no significant difference in the demyelination of the corpus callosum between Cx43 cKO mice and their non-cre littermate controls, while the remyelination process in Cx43 cKO mice was accelerated. Moreover, an increased number of mature oligodendrocytes and an unaltered number of oligodendroglial lineage cells were found in Cx43 cKO mouse lesions. This indicates that oligodendrocyte precursor cell (OPC) differentiation was facilitated by astroglial Cx43 depletion as remyelination progressed. Underlying the latter, there was a down-regulated glial activation and modulated local inflammation as well as a reduction of myelin debris in Cx43 cKO mice. Importantly, 2 weeks of orally administrating boldine, a natural alkaloid that blocks Cx hemichannel activity in astrocytes without affecting gap junctional communication, obviously modulated local inflammation and promoted remyelination. Together, the data suggest that the astrocytic Cx43 hemichannel is negatively involved in the remyelination process by favoring local inflammation. Consequently, inhibiting Cx43 hemichannel functionality may be a potential therapeutic approach for demyelinating diseases in the CNS.
Assuntos
Astrócitos/metabolismo , Conexina 43/metabolismo , Inflamação/metabolismo , Remielinização/fisiologia , Animais , Diferenciação Celular/fisiologia , Sistema Nervoso Central/metabolismo , Doenças Desmielinizantes/patologia , Junções Comunicantes/metabolismo , Camundongos , Bainha de Mielina/metabolismo , Células Precursoras de Oligodendrócitos/metabolismo , Oligodendroglia/metabolismoRESUMO
Posttraumatic stress disorder (PTSD) is a complex mental disorder notable for traumatic experience memory. Although current first-line treatments are linked with clinically important symptom reduction, a large proportion of patients retained to experience considerable residual symptoms, indicating pathogenic mechanism should be illustrated further. Recent studies reported that newly formed myelin could shape neural circuit function and be implicated in fear memory preservation. However, its role in PTSD remains to be elucidated. In this study, we adopted a restraint stress-induced PTSD mouse model and found that PTSD-related neuropsychiatric symptoms were accompanied by increased myelination in the posterior parietal cortex and hippocampus. Fluoxetine, but not risperidone or sertraline, has a more profound rescue effect on neuropsychological behaviors and myelin abnormalities. Further mechanistic experiments revealed that fluoxetine could directly interfere with oligodendroglial differentiation by upregulating Wnt signaling. Our data demonstrated the correlation between PTSD and abnormal myelination, suggesting that the oligodendroglial lineage could be a target for PTSD treatment.
Assuntos
Modelos Animais de Doenças , Fluoxetina , Camundongos Endogâmicos C57BL , Bainha de Mielina , Transtornos de Estresse Pós-Traumáticos , Animais , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Fluoxetina/farmacologia , Fluoxetina/uso terapêutico , Bainha de Mielina/efeitos dos fármacos , Bainha de Mielina/patologia , Bainha de Mielina/metabolismo , Masculino , Camundongos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , Lobo Parietal/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/farmacologiaRESUMO
Astrocytes (ASTs) and oligodendroglial lineage cells (OLGs) are major macroglial cells in the central nervous system. ASTs communicate with each other through connexin (Cx) and Cx-based network structures, both of which allow for quick transport of nutrients and signals. Moreover, ASTs interact with OLGs through connexin (Cx)-mediated networks to modulate various physiological processes in the brain. In this article, following a brief description of the infrastructural basis of the glial networks and exocrine factors by which ASTs and OLGs may crosstalk, we focus on recapitulating how the interactions between these two types of glial cells modulate myelination, and how the AST-OLG interactions are involved in protecting the integrity of the blood-brain barrier (BBB) and regulating synaptogenesis and neural activity. Recent studies further suggest that AST-OLG interactions are associated with myelin-related diseases, such as multiple sclerosis. A better understanding of the regulatory mechanisms underlying AST-OLG interactions may inspire the development of novel therapeutic strategies for related brain diseases.
Assuntos
Encefalopatias , Bainha de Mielina , Humanos , Astrócitos , Oligodendroglia , EncéfaloRESUMO
Oligodendrocyte precursor cells (OPCs) undergo an extensive and coordinated migration in the developing CNS, using the pre-formed scaffold of developed blood vessels as their physical substrate for migration. While OPC association with vasculature is critical for dispersal, equally important for permitting differentiation and proper myelination of target axons is their appropriate and timely detachment, but regulation of this process remains unclear. Here we demonstrate a correlation between the developmental formation of astrocytic endfeet on vessels and the termination of OPC perivascular migration. Ex vivo and in vivo live imaging shows that astrocyte endfeet physically displace OPCs from vasculature, and genetic abrogation of endfoot formation hinders both OPC detachment from vessels and subsequent differentiation. Astrocyte-derived semaphorins 3a and 6a act to repel OPCs from blood vessels at the cessation of their perivascular migration and, in so doing, permit subsequent OPC differentiation by insulating them from a maturation inhibitory endothelial niche.
Assuntos
Células Precursoras de Oligodendrócitos , Astrócitos , Oligodendroglia/fisiologia , Diferenciação Celular/fisiologia , Movimento Celular/fisiologiaRESUMO
Astrocyte maldevelopment is implicated in various neuropsychiatric diseases associated with early life stress. However, the underlying astrocytopathy mechanism, which can result in the psychiatric symptoms, remains unclear. In this study, it is shown that a reduced oligodendrocyte precursor cell (OPC) population accompanies hindered hippocampal astrocytic development in an improved parental isolation mouse model, and that the loss of OPCs suppresses astrocytic network formation and activity. It is further demonstrated that OPC-derived Wnt ligands, in particular Wnt7b, are required for Wnt/ß-catenin pathway-mediated astrocytic development and subsequent effects related to neuronal function. In addition, focal replenishment of Wnt7a/b is sufficient to rescue astrocytic maldevelopment. These results elucidate a Wnt-paracrine-dependent but myelin-independent role of OPCs in regulating astrocytic development, which provides a unique insight into the astrocytopathy mechanism in early life stress, and can be implicated in the pathogenesis of human early life stress-related neuropsychiatric disorders.
Assuntos
Astrócitos/patologia , Células Precursoras de Oligodendrócitos/patologia , Estresse Psicológico/patologia , Animais , Animais Recém-Nascidos , Proliferação de Células , Células Cultivadas , Modelos Animais de Doenças , CamundongosRESUMO
Oligodendrocyte (OL) maturation arrest in human white matter injury contributes significantly to the failure of endogenous remyelination in multiple sclerosis (MS) and newborn brain injuries such as hypoxic ischemic encephalopathy (HIE) that cause cerebral palsy. In this study, we identify an oligodendroglial-intrinsic factor that controls OL maturation specifically in the setting of injury. We find a requirement for the ring finger protein Rnf43 not in normal development but in neonatal hypoxic injury and remyelination in the adult mammalian CNS. Rnf43, but not the related Znrf3, is potently activated by Wnt signaling in OL progenitor cells (OPCs) and marks activated OPCs in human MS and HIE. Rnf43 is required in an injury-specific context, and it promotes OPC differentiation through negative regulation of Wnt signal strength in OPCs at the level of Fzd1 receptor presentation on the cell surface. Inhibition of Fzd1 using UM206 promotes remyelination following ex vivo and in vivo demyelinating injury.
Assuntos
Lesões Encefálicas/genética , Lesões Encefálicas/patologia , Oligodendroglia/patologia , Ubiquitina-Proteína Ligases/genética , Animais , Lesões Encefálicas/metabolismo , Doenças Desmielinizantes/genética , Receptores Frizzled/efeitos dos fármacos , Receptores Frizzled/genética , Humanos , Camundongos , Bainha de Mielina/efeitos dos fármacos , Bainha de Mielina/fisiologia , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , Remielinização/efeitos dos fármacos , Remielinização/genética , Células-Tronco/metabolismo , Células-Tronco/patologia , Substância Branca/metabolismo , Substância Branca/patologia , Via de Sinalização WntRESUMO
Epigenetic alterations and impaired oligodendroglial myelination in the prefrontal cortex have been shown to correlate with behavioral and cognitive dysfunctions in social deprivation. Our previous study demonstrated that quetiapine, an atypical antipsychotic, could promote oligodendroglial differentiation and myelination. However, whether and how quetiapine could be beneficial in modulating aberrant epigenetic alterations in oligodendroglial cells and relieving behavioral alterations from social isolation is unknown. In this study, quetiapine was orally administered in adolescent mice undergoing mild stress of social isolation. We firstly confirmed that social isolation during a novel adolescent period could impair sociability, but not locomotive behaviors in mice. Moreover, quetiapine alleviated myelin deficits, and increased levels of histone methylation (H3K9me3) in mature oligodendroglia in the prefrontal cortex of socially isolated mice. Strikingly, quetiapine treatment significantly increased locomotive activity, and successfully reversed social avoidance behavior of the socially isolated mice. Taken together, our data suggest that quetiapine may rescue behavioral changes from social isolation through modulating epigenetic status toward the beneficial direction for oligodendroglial maturation, providing new insights into the pharmacological mechanism of quetiapine for mental illnesses.
RESUMO
Disruption of the blood-brain barrier (BBB) is critical to initiation and perpetuation of disease in multiple sclerosis (MS). We report an interaction between oligodendroglia and vasculature in MS that distinguishes human white matter injury from normal rodent demyelinating injury. We find perivascular clustering of oligodendrocyte precursor cells (OPCs) in certain active MS lesions, representing an inability to properly detach from vessels following perivascular migration. Perivascular OPCs can themselves disrupt the BBB, interfering with astrocyte endfeet and endothelial tight junction integrity, resulting in altered vascular permeability and an associated CNS inflammation. Aberrant Wnt tone in OPCs mediates their dysfunctional vascular detachment and also leads to OPC secretion of Wif1, which interferes with Wnt ligand function on endothelial tight junction integrity. Evidence for this defective oligodendroglial-vascular interaction in MS suggests that aberrant OPC perivascular migration not only impairs their lesion recruitment but can also act as a disease perpetuator via disruption of the BBB.