TLR9 signalling in microglia attenuates seizure-induced aberrant neurogenesis in the adult hippocampus

• Published in: Nature communications 2015-03, Vol.6 (1), p.6514-6514, Article 6514
• Main Authors: Matsuda, Taito, Murao, Naoya, Katano, Yuki, Juliandi, Berry, Kohyama, Jun, Akira, Shizuo, Kawai, Taro, Nakashima, Kinichi
• Format: Article
• Language: English
• Subjects: 13; 13/100; 13/51; 631/378/1595/1554; 631/378/2571/2572; 631/378/2596/1953; 631/378/368; 96; 96/95; Animals; Cognition; Cognitive Dysfunction - genetics; Cognitive Dysfunction - immunology; Cognitive Dysfunction - pathology; Gene Expression Regulation; Hippocampus - growth & development; Hippocampus - immunology; Hippocampus - metabolism; Hippocampus - pathology; Humanities and Social Sciences; Immunity, Innate - genetics; Male; Membrane Glycoproteins - deficiency; Membrane Glycoproteins - genetics; Membrane Glycoproteins - immunology; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia - immunology; Microglia - metabolism; Microglia - pathology; multidisciplinary; Neurogenesis - genetics; Neurogenesis - immunology; Neurons - immunology; Neurons - metabolism; Neurons - pathology; Science; Science (multidisciplinary); Seizures - genetics; Seizures - immunology; Seizures - metabolism; Seizures - pathology; Severity of Illness Index; Signal Transduction - genetics; Signal Transduction - immunology; Toll-Like Receptor 7 - deficiency; Toll-Like Receptor 7 - genetics; Toll-Like Receptor 7 - immunology; Toll-Like Receptor 9 - deficiency; Toll-Like Receptor 9 - genetics; Toll-Like Receptor 9 - immunology; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - immunology; Tumor Necrosis Factor-alpha - secretion
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms7514

Pathological conditions such as epilepsy cause misregulation of adult neural stem/progenitor populations in the adult hippocampus in mice, and the resulting abnormal neurogenesis leads to impairment in learning and memory. However, how animals cope with abnormal neurogenesis remains unknown. Here we show that microglia in the mouse hippocampus attenuate convulsive seizure-mediated aberrant neurogenesis through the activation of Toll-like receptor 9 (TLR9), an innate immune sensor known to recognize microbial DNA and trigger inflammatory responses. We found that microglia sense self-DNA from degenerating neurons following seizure, and secrete tumour necrosis factor-α, resulting in attenuation of aberrant neurogenesis. Furthermore, TLR9 deficiency exacerbated seizure-induced cognitive decline and recurrent seizure severity. Our findings thus suggest the existence of bidirectional communication between the innate immune and nervous systems for the maintenance of adult brain integrity. Epileptic seizures generate aberrant neurogenesis in the adult mouse hippocampal region but how animals cope with abnormal neurogenesis remains unknown. Here the authors show that microglia are activated through TLR9 signaling and that this leads to sustained expression of TNF-α which attenuates induced aberrant neurogenesis.