Neuroinflammation in Schizophrenia: The Key Role of the WNT/β-Catenin Pathway

Vallée, Alexandre

doi:10.3390/ijms23052810

Cited by 63 publications

(38 citation statements)

References 163 publications

(191 reference statements)

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“…Our previous study demonstrated that Cd 2+ induces microglia activation and neuroinflammation in the brains of zebrafish larvae. Given that the Wnt signaling pathway has been reported to significantly regulate neuroinflammatory responses [ 49 ], we, thus, investigated the role of this pathway in Cd 2+ -induced microgliosis and neuroinflammation. Through in vivo two-photon imaging of the microglia-specific Tg(ApoE: EGFP) transgenic line, we observed and verified that upon Cd 2+ exposure, the microglia in the brain of zebrafish larvae showed distinct branch retraction, changing their morphology from ramified to amoeboid, which is a typical morphological change of microglia activation and neuroimmune response.…”

Section: Resultsmentioning

confidence: 99%

Wnt/β-Catenin Signaling Pathway Is Strongly Implicated in Cadmium-Induced Developmental Neurotoxicity and Neuroinflammation: Clues from Zebrafish Neurobehavior and In Vivo Neuroimaging

Liu

Tian

et al. 2022

IJMS

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Cadmium (Cd) is a toxic heavy metal and worldwide environmental pollutant which seriously threatens human health and ecosystems. It is easy to be adsorbed and deposited in organisms, exerting adverse effects on various organs including the brain. In a very recent study, making full use of a zebrafish model in both high-throughput behavioral tracking and live neuroimaging, we explored the potential developmental neurotoxicity of Cd2+ at environmentally relevant levels and identified multiple connections between Cd2+ exposure and neurodevelopmental disorders as well as microglia-mediated neuroinflammation, whereas the underlying neurotoxic mechanisms remained unclear. The canonical Wnt/β-catenin signaling pathway plays crucial roles in many biological processes including neurodevelopment, cell survival, and cell cycle regulation, as well as microglial activation, thereby potentially presenting one of the key targets of Cd2+ neurotoxicity. Therefore, in this follow-up study, we investigated the implication of the Wnt/β-catenin signaling pathway in Cd2+-induced developmental disorders and neuroinflammation and revealed that environmental Cd2+ exposure significantly affected the expression of key factors in the zebrafish Wnt/β-catenin signaling pathway. In addition, pharmacological intervention of this pathway via TWS119, which can increase the protein level of β-catenin and act as a classical activator of the Wnt signaling pathway, could significantly repress the Cd2+-induced cell cycle arrest and apoptosis, thereby attenuating the inhibitory effects of Cd2+ on the early development, behavior, and activity, as well as neurodevelopment of zebrafish larvae to a certain degree. Furthermore, activation and proliferation of microglia, as well as the altered expression profiles of genes associated with neuroimmune homeostasis triggered by Cd2+ exposure could also be significantly alleviated by the activation of the Wnt/β-catenin signaling pathway. Thus, this study provided novel insights into the cellular and molecular mechanisms of Cd2+ toxicity on the vertebrate central nervous system (CNS), which might be helpful in developing pharmacotherapies to mitigate the neurological disorders resulting from exposure to Cd2+ and many other environmental heavy metals.

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Section: Resultsmentioning

confidence: 99%

Wnt/β-Catenin Signaling Pathway Is Strongly Implicated in Cadmium-Induced Developmental Neurotoxicity and Neuroinflammation: Clues from Zebrafish Neurobehavior and In Vivo Neuroimaging

Liu

Tian

et al. 2022

IJMS

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“…It has been evidenced that neuroinflammation mediated by the NF-κB and related pathways plays a role in the pathogenesis of schizophrenia (Murphy et al, 2021 ; Vallée, 2022 ). Using an MIA model, this study provided the first evidence that epigenetic histone acetylation of H3 and H4 (H3ace and H4ace, respectively) peaking on the promoter region of Rela was involved in the activation of the NF-κB mediated inflammatory pathway in the PFC induced by prenatal Poly I:C exposure.…”

Section: Discussionmentioning

confidence: 99%

“…Neuroinflammation in the central nervous system, particularly the prefrontal cortex (PFC), is involved in the pathogenesis of schizophrenia, in which the nuclear factor kappa-B (NF-κB) and related pathways play an important role (Murphy et al, 2021 ; Vallée, 2022 ). Exposure to polyriboinosinic-polyribocytidylic acid (Poly I:C), a mimic of viral dsRNA, during a specific period of pregnancy is one of the commonly used animal models for studying the pathogenesis of MIA-induced neuropsychiatric disorders, including schizophrenia and autism (Reisinger et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Epigenetic histone acetylation modulating prenatal Poly I:C induced neuroinflammation in the prefrontal cortex of rats: a study in a maternal immune activation model

Lian

Chen

et al. 2022

Front. Cell. Neurosci.

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Introduction: Neuroinflammation in the central nervous system, particularly the prefrontal cortex (PFC), plays a role in the pathogenesis of schizophrenia, which has been found to be associated with maternal immune activation (MIA). Recent evidence suggests that epigenetic regulation involves in the MIA-induced neurodevelopmental disturbance. However, it is not well-understood how epigenetic modulation is involved in the neuroinflammation and pathogenesis of schizophrenia.Methods: This study explored the modulation of histone acetylation in both neuroinflammation and neurotransmission using an MIA rat model induced by prenatal polyriboinosinic-polyribocytidylic acid (Poly I:C) exposure, specifically examining those genes that were previously observed to be impacted by the exposure, including a subunit of nuclear factor kappa-B (Rela), Nod-Like-Receptor family Pyrin domain containing 3 (Nlrp3), NMDA receptor subunit 2A (Grin2a), 5-HT2A (Htr2a), and GABAA subunit β3 (Gabrb3).Results: Our results revealed global changes of histone acetylation on H3 (H3ace) and H4 (H4ace) in the PFC of offspring rats with prenatal Poly I:C exposure. In addition, it revealed enhancement of both H3ace and H4ace binding on the promoter region of Rela, as well as positive correlations between Rela and genes encoding histone acetyltransferases (HATs) including CREB-binding protein (CBP) and E1A-associated protein p300 (EP300). Although there was no change in H3ace or H4ace enrichment on the promoter region of Nlrp3, a significant enhancement of histone deacetylase 6 (HDAC6) binding on the promoter region of Nlrp3 and a positive correlation between Nlrp3 and Hdac6 were also observed. However, prenatal Poly I:C treatment did not lead to any specific changes of H3ace and H4ace on the promoter region of the target genes encoding neurotransmitter receptors in this study.Discussion: These findings demonstrated that epigenetic modulation contributes to NF-κB/NLRP3 mediated neuroinflammation induced by prenatal Poly I:C exposure via enhancement of histone acetylation of H3ace and H4ace on Rela and HDAC6-mediated NLRP3 transcriptional activation. This may further lead to deficits in neurotransmissions and schizophrenia-like behaviors observed in offspring.

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“…These cytokines serve to contain and resolve the inflammatory foci through activation of local and systemic inflammatory responses. Pro-inflammatory cytokines may directly modulate neuronal activity in various classes of neurons in CNS, including dopaminergic neurons [ 97 ]. The major pro-inflammatory cytokines that are responsible for early responses are interleukin 1 alpha (IL1-α), interleukin 1 β (IL1-β), interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α).…”

Section: Cytokines Alteration In Treatment-resistant Schizophreniamentioning

confidence: 99%

Cytokine Imbalance as a Biomarker of Treatment-Resistant Schizophrenia

Shnayder

Khasanova

Strelnik

et al. 2022

IJMS

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Treatment-resistant schizophrenia (TRS) is an important and unresolved problem in biological and clinical psychiatry. Approximately 30% of cases of schizophrenia (Sch) are TRS, which may be due to the fact that some patients with TRS may suffer from pathogenetically “non-dopamine” Sch, in the development of which neuroinflammation is supposed to play an important role. The purpose of this narrative review is an attempt to summarize the data characterizing the patterns of production of pro-inflammatory and anti-inflammatory cytokines during the development of therapeutic resistance to APs and their pathogenetic and prognostic significance of cytokine imbalance as TRS biomarkers. This narrative review demonstrates that the problem of evaluating the contribution of pro-inflammatory and anti-inflammatory cytokines to maintaining or changing the cytokine balance can become a new key in unlocking the mystery of “non-dopamine” Sch and developing new therapeutic strategies for the treatment of TRS and psychosis in the setting of acute and chronic neuroinflammation. In addition, the inconsistency of the results of previous studies on the role of pro-inflammatory and anti-inflammatory cytokines indicates that the TRS biomarker, most likely, is not the serum level of one or more cytokines, but the cytokine balance. We have confirmed the hypothesis that cytokine imbalance is one of the most important TRS biomarkers. This hypothesis is partially supported by the variable response to immunomodulators in patients with TRS, which were prescribed without taking into account the cytokine balance of the relation between serum levels of the most important pro-inflammatory and anti-inflammatory cytokines for TRS.

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Neuroinflammation in Schizophrenia: The Key Role of the WNT/β-Catenin Pathway

Cited by 63 publications

References 163 publications

Wnt/β-Catenin Signaling Pathway Is Strongly Implicated in Cadmium-Induced Developmental Neurotoxicity and Neuroinflammation: Clues from Zebrafish Neurobehavior and In Vivo Neuroimaging

Wnt/β-Catenin Signaling Pathway Is Strongly Implicated in Cadmium-Induced Developmental Neurotoxicity and Neuroinflammation: Clues from Zebrafish Neurobehavior and In Vivo Neuroimaging

Epigenetic histone acetylation modulating prenatal Poly I:C induced neuroinflammation in the prefrontal cortex of rats: a study in a maternal immune activation model

Cytokine Imbalance as a Biomarker of Treatment-Resistant Schizophrenia

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