Gene Expression Profile of Olfactory Transduction Signaling in an Animal Model of Human Multiple Sclerosis

Kim, Jeong-Tae; Ahn, Meejung; Choi, Yu-Mi; Ekanayake, Poornima; Park, Chul Min; Moon, Changjong; Jung, Kyungsook; Tanaka, Akane; Matsuda, Hiroshi; Shin, Taekyun

doi:10.5607/en.2019.28.1.74

Cited by 13 publications

(7 citation statements)

References 45 publications

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“…EAE induces inflammation within the CNS ( Kim et al, 2019 ; Pierson et al, 2012 ; Zorzella-Pezavento et al, 2013 ). We previously documented inflammatory pathway activation in the hippocampus during the chronic phase of EAE ( Weerasinghe-Mudiyanselage et al, 2022b ).…”

Section: Resultsmentioning

confidence: 99%

Changes in structural plasticity of hippocampal neurons in an animal model of multiple sclerosis

D.E. Weerasinghe-Mudiyanselage,

Kang,

Kim

et al. 2024

Zoological Research

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Structural plasticity is critical for the functional diversity of neurons in the brain. Experimental autoimmune encephalomyelitis (EAE) is the most commonly used model for multiple sclerosis (MS), successfully mimicking its key pathological features (inflammation, demyelination, axonal loss, and gliosis) and clinical symptoms (motor and non-motor dysfunctions). Recent studies have demonstrated the importance of synaptic plasticity in EAE pathogenesis. In the present study, we investigated the features of behavioral alteration and hippocampal structural plasticity in EAE-affected mice in the early phase (11 days post-immunization, DPI) and chronic phase (28 DPI). EAE-affected mice exhibited hippocampus-related behavioral dysfunction in the open field test during both early and chronic phases. Dendritic complexity was largely affected in the cornu ammonis 1 (CA1) and CA3 apical and dentate gyrus (DG) subregions of the hippocampus during the chronic phase, while this effect was only noted in the CA1 apical subregion in the early phase. Moreover, dendritic spine density was reduced in the hippocampal CA1 and CA3 apical/basal and DG subregions in the early phase of EAE, but only reduced in the DG subregion during the chronic phase. Furthermore, mRNA levels of proinflammatory cytokines ( Il1β , Tnfα , and Ifnγ ) and glial cell markers ( Gfap and Cd68 ) were significantly increased, whereas the expression of activity-regulated cytoskeleton-associated protein (ARC) was reduced during the chronic phase. Similarly, exposure to the aforementioned cytokines in primary cultures of hippocampal neurons reduced dendritic complexity and ARC expression. Primary cultures of hippocampal neurons also showed significantly reduced extracellular signal-regulated kinase (ERK) phosphorylation upon treatment with proinflammatory cytokines. Collectively, these results suggest that autoimmune neuroinflammation alters structural plasticity in the hippocampus, possibly through the ERK-ARC pathway, indicating that this alteration may be associated with hippocampal dysfunctions in EAE.

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Section: Resultsmentioning

confidence: 99%

Changes in structural plasticity of hippocampal neurons in an animal model of multiple sclerosis

D.E. Weerasinghe-Mudiyanselage,

Kang,

Kim

et al. 2024

Zoological Research

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“…Mice were monitored daily for changes in their weights and clinical signs of EAE, which were graded as follows: grade 0 (G.0), no signs; G.1, floppy tail; G.2, mild paraparesis; G.3, severe paraparesis; G.4, tetraparesis; and G.5, moribund or death (Kim et al 2019 ). At 28 DPI, retinal tissues were collected from both control and EAE mice to analyze histopathological changes and gene expression profiles.…”

Section: Methodsmentioning

confidence: 99%

“…Immunohistochemistry was performed using the same protocol used in a previous study (Kim et al 2019 ). The primary antibody (#019-19741; Wako Pure Chemical Industries, Ltd., Osaka, Japan) was diluted 1:1,000 against ionized calcium-binding adapter molecule 1 (Iba1), as a marker for microglia and macrophages.…”

Section: Methodsmentioning

confidence: 99%

Retinal transcriptome profiling identifies novel candidate genes associated with visual impairment in a mouse model of multiple sclerosis

Hong,

Weerasinghe-Mudiyanselage,

Kang

et al. 2023

Animal Cells and Systems

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Visual impairment is occasionally observed in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Although uveitis and optic neuritis have been reported in MS and EAE, the precise mechanisms underlying the pathogenesis of these visual impairments remain poorly understood. This study aims to identify differentially expressed genes (DEGs) in the retinas of mice with EAE to identify genes that may be implicated in EAE-induced visual impairment. Fourteen adult mice were injected with myelin oligodendrocyte glycoprotein 35–55 to induce the EAE model. Transcriptomes of retinas with EAE were analyzed by RNA-sequencing. Gene expression analysis revealed 347 DEGs in the retinas of mice with EAE: 345 were upregulated, and 2 were downregulated (adjusted p -value < 0.05 and absolute log 2 fold change > 1). Gene ontology (GO) analysis showed that the upregulated genes in the retinas of mice with EAE were primarily related to immune responses, responses to external biotic stimuli, defense responses, and leukocyte-mediated immunity in the GO biological process. The expression of six upregulated hub genes ( c1qb, ctss, itgam, itgb2, syk , and t yrobp) from the STRING analysis and the two significantly downregulated DEGs ( hapln1 and ndst4 ) were validated by reverse transcription-quantitative polymerase chain reaction. In addition, gene set enrichment analysis showed that the negatively enriched gene sets in EAE-affected retinas were associated with the neuronal system and phototransduction cascade. This study provides novel molecular evidence for visual impairments in EAE and indicates directions for further research to elucidate the mechanisms of these visual impairments in MS.

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“…EAE was induced in mice ( n = 10) as previously described [ 72 ]. Briefly, the EAE group was immunized with 1 mg/mL of MOG 35–55 peptide (purity > 96.44%; #051716, GL Biochem Ltd., Shanghai, China) emulsified in complete Freund’s adjuvant (CFA; #F5881, Sigma-Aldrich, St. Louis, MO, USA) supplemented with 5 mg/mL of Mycobacterium tuberculosis H37Ra (#BD231141, Difco Laboratories Inc., Franklin Lakes, NJ, USA) by subcutaneous injection into the hind flank.…”

Section: Methodsmentioning

confidence: 99%

Transcriptome Profiling in the Hippocampi of Mice with Experimental Autoimmune Encephalomyelitis

Weerasinghe-Mudiyanselage

Kang

Kim

et al. 2022

IJMS

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Experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), approximates the key histopathological, clinical, and immunological features of MS. Hippocampal dysfunction in MS and EAE causes varying degrees of cognitive and emotional impairments and synaptic abnormalities. However, the molecular alterations underlying hippocampal dysfunctions in MS and EAE are still under investigation. The purpose of this study was to identify differentially expressed genes (DEGs) in the hippocampus of mice with EAE in order to ascertain potential genes associated with hippocampal dysfunction. Gene expression in the hippocampus was analyzed by RNA-sequencing and validated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Gene expression analysis revealed 1202 DEGs; 1023 were upregulated and 179 were downregulated in the hippocampus of mice with EAE (p-value < 0.05 and fold change >1.5). Gene ontology (GO) analysis showed that the upregulated genes in the hippocampi of mice with EAE were associated with immune system processes, defense responses, immune responses, and regulation of immune responses, whereas the downregulated genes were related to learning or memory, behavior, and nervous system processes in the GO biological process. The expressions of hub genes from the search tool for the retrieval of interacting genes/proteins (STRING) analysis were validated by RT-qPCR. Additionally, gene set enrichment analysis showed that the upregulated genes in the hippocampus were associated with inflammatory responses: interferon-γ responses, allograft rejection, interferon-α responses, IL6_JAK_STAT3 signaling, inflammatory responses, complement, IL2_STAT5 signaling, TNF-α signaling via NF-κB, and apoptosis, whereas the downregulated genes were related to synaptic plasticity, dendritic development, and development of dendritic spine. This study characterized the transcriptome pattern in the hippocampi of mice with EAE and signaling pathways underpinning hippocampal dysfunction. However, further investigation is needed to determine the applicability of these findings from this rodent model to patients with MS. Collectively, these results indicate directions for further research to understand the mechanisms behind hippocampal dysfunction in EAE.

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Gene Expression Profile of Olfactory Transduction Signaling in an Animal Model of Human Multiple Sclerosis

Cited by 13 publications

References 45 publications

Changes in structural plasticity of hippocampal neurons in an animal model of multiple sclerosis

Changes in structural plasticity of hippocampal neurons in an animal model of multiple sclerosis

Retinal transcriptome profiling identifies novel candidate genes associated with visual impairment in a mouse model of multiple sclerosis

Transcriptome Profiling in the Hippocampi of Mice with Experimental Autoimmune Encephalomyelitis

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