Inactivation of microglial LXRβ in early postnatal mice impairs microglia homeostasis and causes long-lasting cognitive dysfunction
Abstract
Microglia, the largest population of brain immune cells, play an essential role in regulating neuroinflammation by removing foreign materials and debris and in cognition by pruning synapses. Since liver X receptor β (LXRβ) has been identified as a regulator of microglial homeostasis, this study examined whether its removal from microglia affects neuroinflammation and cognitive function. We used a cell-specific tamoxifen-inducible Cre-loxP-mediated recombination to remove LXRβ from microglia specifically. We now report that ablation of LXRβ in microglia in early postnatal life led to a reduction in microglial numbers, distinct morphological changes indicative of microglial activation, and enhanced synapse engulfment accompanied by cognitive deficits. Removal of LXRβ from microglia in adult mice caused no cognitive defects. RNAseq analysis of microglia revealed that loss of LXRβ led to reduced expression of SAll1, a master regulator of microglial homeostasis, while increasing expression of genes associated with microglial activation and CNS disease. This study demonstrates distinctly different functions of microglial LXRβ in developing and adult mice and points to long-term consequences of defective LXRβ signaling in microglia in early life.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (16)
Keyi Lv
Department of Military Cognitive Psychology, School of Psychology, Third Military Medical University (Army Medical University)
Yi Luo
State Key Laboratory of Green Chemical Engineering and Industrial Catalysis
Tianyao Liu
Department of Military Cognitive Psychology, School of Psychology, Third Military Medical University (Army Medical University)
Meiling Xia
Department of Military Cognitive Psychology, School of Psychology, Third Military Medical University (Army Medical University)
Hong Gong
Department of Military Cognitive Psychology, School of Psychology, Third Military Medical University (Army Medical University)
Dandan Zhang
Xuan Chen
Xin Jiang
Yulong Liu
Jiayin Liu
Department of Military Cognitive Psychology, School of Psychology, Third Military Medical University (Army Medical University)
Yulong Cai
GRINM (Guangdong) Institute for Advanced Materials and Technology
Per Antonson
Center for Innovative Medicine, Department of Biosciences and Nutrition, Karolinska Institutet, Novum
Margaret Warner
Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston
Haiwei Xu
Southwest Eye Hospital, Southwest Hospital, Third Military Medical University (Army Medical University)
Jan-Ake Gustafsson
Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston
Xiaotang Fan
Department of Military Cognitive Psychology, School of Psychology, Third Military Medical University (Army Medical University)