Kummer Kai, Choconta Jeiny Luna, Edenhofer Marie-Luise, Bajpai Archana, Dharmalingam Gopuraja, Kalpachidou Theodora, Collier David A, Kress Michaela
Institute of Physiology, Medical University of Innsbruck, Innsbruck, Austria.
Institute of Physiology, Medical University of Innsbruck, Innsbruck, Austria.
Neurobiol Dis. 2025 Feb;205:106797. doi: 10.1016/j.nbd.2025.106797. Epub 2025 Jan 7.
Fabry disease (FD) patients are known to be at high risk of developing neuropsychiatric symptoms such as anxiety, depression and cognitive deficits. Despite this, they are underdiagnosed and inadequately treated. It is unknown whether these symptoms arise from pathological glycosphingolipid deposits or from cerebrovascular abnormalities affecting neuronal functions in the central nervous system. We therefore aimed to fill this knowledge gap by exploring a transgenic FD mouse model with a combination of behavior, transcriptomic, functional and morphological assessments, with a particular focus on the hippocampus.
Male FD mice exhibited increased anxiety-like behavior in the open field test, accompanied by a reduced exploratory drive in the Barnes maze, which could be related to the increased deposition of globotriaosylceramide (Gb3) identified in the dentate gyrus (DG). Hippocampus single-cell sequencing further revealed that Gb3 accumulation was associated with differential gene expression in neuronal and non-neuronal cell populations with granule, excitatory and interneurons, as well as microglia and endothelial cells as the main clusters with the most dysregulated genes. Particularly FD hippocampal neurons showed decreased electrical baseline activity in the DG and increased activity in the CA3 region of acutely dissected hippocampal slices.
Our study highlights transcriptional and functional alterations in non-neuronal and neuronal cell clusters in the hippocampus of FD mice, which are suggested to be causally related to anxiety-like behavior developing as a consequence of FD pathology in mouse models of the disease and in patients.
已知法布里病（FD）患者出现焦虑、抑郁和认知缺陷等神经精神症状的风险很高。尽管如此，他们仍未得到充分诊断和治疗。目前尚不清楚这些症状是由病理性糖鞘脂沉积引起的，还是由影响中枢神经系统神经元功能的脑血管异常引起的。因此，我们旨在通过对一种转基因FD小鼠模型进行行为、转录组学、功能和形态学评估，以填补这一知识空白，特别关注海马体。
雄性FD小鼠在旷场试验中表现出焦虑样行为增加，同时在巴恩斯迷宫中的探索驱动力降低，这可能与齿状回（DG）中鉴定出的球三糖神经酰胺（Gb3）沉积增加有关。海马单细胞测序进一步显示，Gb3积累与神经元和非神经元细胞群体中的差异基因表达有关，其中颗粒细胞、兴奋性神经元和中间神经元，以及小胶质细胞和内皮细胞是基因失调最严重的主要细胞簇。特别是FD海马神经元在急性分离的海马切片的DG中显示出电基线活动降低，而在CA3区域显示出活动增加。
我们的研究突出了FD小鼠海马体中非神经元和神经元细胞簇的转录和功能改变，这些改变被认为与该疾病小鼠模型和患者中由于FD病理导致的焦虑样行为有因果关系。
