Abnormal brain structure and behavior in MyD88-deficient mice

Patricia Schroeder; Marion Rivalan; Sami Zaqout; Christina Krüger; Jutta Schüler; Melissa Long; Andreas Meisel; York Winter; Angela M Kaindl; Seija Lehnardt

doi:10.1016/j.bbi.2020.09.024

Abnormal brain structure and behavior in MyD88-deficient mice

Brain Behav Immun. 2021 Jan:91:181-193. doi: 10.1016/j.bbi.2020.09.024. Epub 2020 Sep 28.

Authors

Affiliations

¹ Institute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
² Institute of Biology, Humboldt-Universität, Berlin, Germany; Animal Outcome Core Facility of the Cluster of Excellence, NeuroCure, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität and Humboldt-Universität, Berlin, and Berlin Institute of Health, Berlin, Germany.
³ Basic Medical Science Department, College of Medicine, QU Health, Qatar University, Doha, Qatar.
⁴ Animal Outcome Core Facility of the Cluster of Excellence, NeuroCure, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität and Humboldt-Universität, Berlin, and Berlin Institute of Health, Berlin, Germany.
⁵ Department of Neurology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
⁶ Institute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany; Department of Pediatric Neurology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany; Center for Chronically Sick Children, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
⁷ Institute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany; Department of Neurology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany. Electronic address: seija.lehnardt@charite.de.

PMID: 33002631
DOI: 10.1016/j.bbi.2020.09.024

Abstract

While the original protein Toll in Drosophila melanogaster regulates both host defense and morphogenesis, the role of its ortholog Toll-like receptors (TLRs), the interleukin 1 receptor (IL-1R) family, and the associated signaling pathways in mammalian brain development and structure is poorly understood. Because the adaptor protein myeloid differentiation primary response protein 88 (MyD88) is essential for downstream signaling of most TLRs and IL-1R, we systematically investigated the effect of MyD88 deficiency on murine brain structure during development and on behavior. In neonatal Myd88^-/- mice, neocortical thickness was reduced, while density of cortical neurons was increased. In contrast, microglia, astrocyte, oligodendrocyte, and proliferating cell numbers were unchanged in these mice compared to wild-type mice. In adult Myd88^-/- mice, neocortical thickness was unaltered, but neuronal density in neocortex and hippocampus was increased. Neuron arborization was less pronounced in adult Myd88^-/- mice compared to wild-type animals. In addition, numbers of microglia and proliferating cells were increased in the neocortex and subventricular zone, respectively, with unaltered astrocyte and oligodendrocyte numbers, and myelinization was enhanced in the adult Myd88^-/- neocortex. These morphologic changes in the brain of adult Myd88^-/- mice were accompanied by specific behavioral traits, such as decreased locomotor activity, increased anxiety-like behavior, but normal day/light activity, satisfactory learning, short- and long-term spatial memory, potential cognitive inflexibility, and increased hanging and locomotor behavior within their home cage. Taken together, MyD88 deficiency results in morphologic and cellular changes in the mouse brain, as well as in altered natural and specific behaviors. Our data indicate a pathophysiological significance of MyD88 for mammalian CNS development, structure, and function.

Keywords: Brain development; Mouse behavior; MyD88; Neocortex; Toll; Toll-like receptors.

Publication types

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

MeSH terms

Adaptor Proteins, Signal Transducing
Animals
Behavior, Animal*
Brain / pathology*
Mice
Mice, Inbred C57BL
Mice, Knockout
Myeloid Differentiation Factor 88* / genetics
Myeloid Differentiation Factor 88* / metabolism
Receptors, Interleukin-1 / metabolism

Substances

Adaptor Proteins, Signal Transducing
Myd88 protein, mouse
Myeloid Differentiation Factor 88
Receptors, Interleukin-1