Synapse Remodeling, Compliments of the Complement System

Division of Biological Sciences, Section of Neurobiology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Cell (Impact Factor: 32.24). 01/2008; 131(6):1034-6. DOI: 10.1016/j.cell.2007.11.031
Source: PubMed


A growing body of evidence indicates that some proteins known for their immune functions also have distinct nonimmune functions in the normal uninjured central nervous system. In this issue, Stevens et al. (2007) demonstrate an unexpected requirement for molecules of the complement cascade in the remodeling of synaptic connections in the developing visual system.

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Available from: Lisa M Boulanger, Oct 08, 2015
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    • "They are distributed throughout the brain and retina, represent approximately 12% of the adult brain cells, and play a pivotal role in the innate immune response [1]. In normal conditions, microglia support synaptogenesis through the local synthesis of neurotrophic factors [2], [3] and the regulation of synaptic transmission and remodeling [4],[5]. In response to acute neurodegenerative disease, they transform from a ramified basal homeostatic phenotype to an activated phagocytic phenotype and release pro-inflammatory mediators, such as IL1β and TNFα. "
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    ABSTRACT: Background and Objective Tetrandrine (TET) is a bisbenzylisoquinoline alkaloid extracted from Stephania tetrandra Moore. Recent studies have suggested that TET can reduce the inflammatory response in microglia, but the mechanisms remain unclear. The aim of this study is to investigate whether TET can inhibit lipopolysaccharide (LPS)-induced microglial activation and clarify its possible mechanisms. Study Design/Materials and Methods Cell viability assays and cell apoptosis assays were used to determine the working concentrations of TET. Then, BV2 cells were seeded and pretreated with TET for 2 h. LPS was then added and incubated for an additional 24 hours. qRT-PCR and ELISA were used to measure the mRNA or protein levels of IL1β and TNFα. Western blotting was utilized to quantify the expression of CD11b and cell signaling proteins. Results TET at optimal concentrations (0.1 µM, 0.5 µM or 1 µM) did not affect the cell viability. After TET pretreatment, the levels of IL1β and TNFα (both in transcription and translation) were significantly inhibited in a dose-dependent manner. Further studies indicated that phospho-p65, phospho-IKK, and phospho-ERK 1/2 expression were also suppressed by TET. Conclusions Our results indicate that TET can effectively suppress microglial activation and inhibit the production of IL1β and TNFα by regulating the NF-kB and ERK signaling pathways. Together with our previous studies, we suggest that TET would be a promising candidate to effectively suppress overactivated microglia and alleviate neurodegeneration in glaucoma.
    PLoS ONE 08/2014; 9(8):e102522. DOI:10.1371/journal.pone.0102522 · 3.23 Impact Factor
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    • "Notably, C1qa, C1qb, C1qc, H2-Aa (HLA-DQA1), and H2-Ab1 (HLA-DQB1) were upregulated in the brains of both Shn-2 KO mice and patients with schizophrenia. C1q is proposed to act as a spreading ‘punishment signals' that bind to weaker synapses resulting in their physical removal (Fourgeaud and Boulanger, 2007). In this regard, it is of interest to note that the expression of the genes related to ‘synaptic transmission,' the dysregulation of which is also thought to be involved in schizophrenia (Mirnics et al, 2001; Stephan et al, 2006), tended to be downregulated in the brains of both Shn-2 KO mice and schizophrenic patients (Supplementary Table 3). "
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    ABSTRACT: Schnurri-2 (Shn-2), an NF-kappa B site-binding protein, tightly binds to the enhancers of major histocompatibility complex (MHC) class I genes and inflammatory cytokines, which have been shown to harbor common variant single nucleotide polymorphisms associated with schizophrenia. Although genes related to immunity are implicated in schizophrenia, there has been no study showing that their mutation or knockout results in schizophrenia. Here, we show that Shn-2 knockout mice have behavioral abnormalities that resemble those of schizophrenics. The mutant brain demonstrated multiple schizophrenia-related phenotypes, including transcriptome/proteome changes similar to those of postmortem schizophrenia patients, decreased parvalbumin and GAD67 levels, increased theta power on electroencephalograms, and a thinner cortex. Dentate gyrus granule cells failed to mature in mutants, a previously proposed endophenotype of schizophrenia. Shn-2 knockout mice also exhibited mild chronic inflammation of the brain, as evidenced by increased inflammation markers (including GFAP and NADH/NADPH oxidase p22 phox), and genome-wide gene expression patterns similar to various inflammatory conditions. Chronic administration of anti-inflammatory drugs reduced hippocampal GFAP expression, and reversed deficits in working memory and nest building behaviors in Shn-2 KO mice. These results suggest that genetically-induced changes in immune system can be a predisposing factor in schizophrenia.Neuropsychopharmacology accepted article preview online, 6 February 2013; doi:10.1038/npp.2013.38.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 02/2013; 38(8). DOI:10.1038/npp.2013.38 · 7.05 Impact Factor
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    • "Expression of major histocompatibility complex class I (MHC I) by neurons and glial cells has been implicated in the synaptic elimination process during development and after lesions in adulthood [1-3]. More recently, molecules from the classic complement pathway have also been implicated in the process of refinement of neural circuits and as important players in the response to peripheral nerve injury [4]. This classic model for studying the retrograde reaction to axon transection has been widely used, and has improved our understanding of the mechanisms underlying synapse elimination and of the interactions between neurons and glial cells after injury [2,5,6]. "
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    ABSTRACT: Background Glial cells are involved in the synaptic elimination process that follows neuronal lesions, and are also responsible for mediating the interaction between the nervous and immune systems. Neurons and glial cells express Toll-like receptors (TLRs), which may affect the plasticity of the central nervous system (CNS). Because TLRs might also have non-immune functions in spinal-cord injury (SCI), we aimed to investigate the influence of TLR2 and TLR4 on synaptic plasticity and glial reactivity after peripheral nerve axotomy. Methods The lumbar spinal cords of C3H/HePas wild-type (WT) mice, C3H/HeJ TLR4-mutant mice, C57BL/6J WT mice, and C57BL/6J TLR2 knockout (KO) mice were studied after unilateral sciatic nerve transection. The mice were killed via intracardiac perfusion, and the spinal cord was processed for immunohistochemistry, transmission electron microscopy (TEM), western blotting, cell culture, and reverse transcriptase PCR. Primary cultures of astrocytes from newborn mice were established to study the astrocyte response in the absence of TLR2 and the deficiency of TLR4 expression. Results The results showed that TLR4 and TLR2 expression in the CNS may have opposite effects on the stability of presynaptic terminals in the spinal cord. First, TLR4 contributed to synaptic preservation of terminals in apposition to lesioned motor neurons after peripheral injury, regardless of major histocompatibility complex class I (MHC I) expression. In addition, in the presence of TLR4, there was upregulation of glial cell-derived neurotrophic factor and downregulation of interleukin-6, but no morphological differences in glial reactivity were seen. By contrast, TLR2 expression led to greater synaptic loss, correlating with increased astrogliosis and upregulation of pro-inflammatory interleukins. Moreover, the absence of TLR2 resulted in the upregulation of neurotrophic factors and MHC I expression. Conclusion TLR4 and TLR2 in the CNS may have opposite effects on the stability of presynaptic terminals in the spinal cord and in astroglial reactions, indicating possible roles for these proteins in neuronal and glial responses to injury.
    Journal of Neuroinflammation 10/2012; 9(1):240. DOI:10.1186/1742-2094-9-240 · 5.41 Impact Factor
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