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

Zool Res. 2024 Mar 18;45(2):398-414. doi: 10.24272/j.issn.2095-8137.2023.309.


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.

结构可塑性对于大脑中神经元的功能多样性至关重要。实验性自身免疫性脑脊髓炎(experimental autoimmune encephalomyelitis,EAE)是最常用的多发性硬化(multiple sclerosis,MS)模型,成功模拟了其主要病理特征(炎症、脱髓鞘、轴索丢失和胶质增生)和临床症状(运动和非运动功能障碍)。近期的研究已经证明了EAE发病机制中突触可塑性的重要性。本研究中,我们调查了EAE患者小鼠早期(免疫后11天,days post-immunization,DPI)和慢性期(28 DPI)的行为改变和海马结构可塑性的特点。EAE患者小鼠在早期和慢性期的开放场测试中表现出与海马相关的行为功能障碍。在慢性期,海马的cornu ammonis 1(CA1)和CA3顶部以及齿状回(dentate gyrus,DG)亚区的树突复杂性受到了很大影响,而在早期只有CA1顶部亚区受到了影响。而且,EAE早期海马CA1和CA3顶部/基底以及DG亚区的树突棘密度减少,而在慢性期只有DG亚区减少。此外,在慢性期,促炎细胞因子(Il1β、Tnfα和Ifnγ)和胶质细胞标记物(Gfap和Cd68)的mRNA水平明显增加,而活性调节的细胞骨架相关蛋白(activity-regulated cytoskeleton-associated protein ,ARC)的表达降低。同样,在海马神经元的原代培养中接触上述细胞因子会减少树突复杂性和ARC的表达。海马神经元的原代培养在接受促炎细胞因子处理后,外周信号调控激酶(extracellular signal-regulated kinase ,ERK)磷酸化显著减少。综上所述,这些结果表明自身免疫性神经炎症会改变海马的结构可塑性,可能通过ERK-ARC途径进行,表明这种变化可能与EAE中的海马功能障碍相关。.

Keywords: Activity-regulated cytoskeleton-associated protein; Anxiety-like behavior; Experimental autoimmune encephalomyelitis; Hippocampal dysfunction; Neuroinflammation.

MeSH terms

  • Animals
  • Cytokines / metabolism
  • Encephalomyelitis, Autoimmune, Experimental* / metabolism
  • Encephalomyelitis, Autoimmune, Experimental* / pathology
  • Encephalomyelitis, Autoimmune, Experimental* / veterinary
  • Hippocampus / metabolism
  • Mice
  • Multiple Sclerosis* / metabolism
  • Multiple Sclerosis* / pathology
  • Multiple Sclerosis* / veterinary
  • Neurons / pathology
  • Rodent Diseases* / metabolism
  • Rodent Diseases* / pathology


  • Cytokines

Grants and funding

This study was supported by the National Research Foundation (NRF) of Korea Grant funded by the Korean Government (NRF-2022R1A2C100402212; RS-2023-00219517)