Toll-like receptor-2 gene knockout results in neurobehavioral dysfunctions and multiple brain structural and functional abnormalities in mice

Yuting Hu; Xiaoyu Sun; Shang Wang; Chao Zhou; Li Lin; Xiaohui Ding; Jingjing Han; Yan Zhou; Guoliang Jin; Yuqiao Wang; Wei Zhang; Hongjuan Shi; Zuohui Zhang; Xinxin Yang; Fang Hua

doi:10.1016/j.bbi.2020.10.004

Toll-like receptor-2 gene knockout results in neurobehavioral dysfunctions and multiple brain structural and functional abnormalities in mice

Brain Behav Immun. 2021 Jan:91:257-266. doi: 10.1016/j.bbi.2020.10.004. Epub 2020 Oct 16.

Authors

Yuting Hu¹, Xiaoyu Sun¹, Shang Wang¹, Chao Zhou¹, Li Lin¹, Xiaohui Ding², Jingjing Han¹, Yan Zhou¹, Guoliang Jin¹, Yuqiao Wang¹, Wei Zhang¹, Hongjuan Shi¹, Zuohui Zhang¹, Xinxin Yang¹, Fang Hua³

Affiliations

¹ Department of Neurology, Affiliated Hospital of Xuzhou Medical University, China; Institute of Neurological Diseases, Xuzhou Medical University, China.
² Department of Histology and Embryology, Shenyang Medical College, China.
³ Department of Neurology, Affiliated Hospital of Xuzhou Medical University, China; Institute of Neurological Diseases, Xuzhou Medical University, China. Electronic address: huafang@xzhmu.edu.cn.

PMID: 33069798
DOI: 10.1016/j.bbi.2020.10.004

Abstract

Objective: Toll-like receptor-2 (TLR2), a member of TLR family, plays an important role in the induction and regulation of immune/inflammation. TLR2 gene knockout (TLR2KO) mice have been widely used for animal models of neurological diseases. Since there is close relationship between immune system and neurobehavioral functions, it is important to clarify the exact role of TLR2 defect itself in neurobehavioral functions. The present study aimed to investigate the effect of TLR2KO on neurobehavioral functions in mice and the mechanisms underlying the observed changes.

Methods: Male TLR2KO and wild type (WT) mice aged 3, 7, and 12 months were used for neurobehavioral testing and detection of protein expression by Western blot. Brain magnetic resonance imaging (MRI), electrophysiological recording, and Evans blue (EB) assay were applied to evaluate regional cerebral blood flow (rCBF), synaptic function, and blood-brain barrier (BBB) integrity in 12-month-old TLR2KO and age-matched WT mice.

Results: Compared to WT mice, TLR2KO mice showed decreased cognitive function and locomotor activity, as well as increased anxiety, which developed from middle age (before 7-month-old) to old age. In addition, significantly reduced regional cerebral blood flow (rCBF), inhibited long-term potentiation (LTP), and increased blood-brain barrier (BBB) permeability were observed in 12-month-old TLR2KO mice. Furthermore, compared with age-matched WT mice, significant reduction in protein levels of tight junction proteins (ZO-1, Occludin, and Claudin-5) and increased neurofilament protein (SMI32) were observed in 7 and 12-month-old TLR2KO mice, and that myelin basic protein (MBP) decreased in 12-month-old TLR2KO mice.

Conclusion: Our data demonstrated that TLR2 defect resulted in significantly observable neurobehavioral dysfunctions in mice starting from middle age, as well as multiple abnormalities in brain structure, function, and molecular metabolism.

Keywords: Blood-brain barrier; Neurobehavioral function; Synaptic function; TLR2; rCBF.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Blood-Brain Barrier*
Brain*
Gene Knockout Techniques
Male
Mice
Mice, Inbred C57BL
Mice, Knockout