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

Abstract

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-a, 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.

Exercise as a pro-cognitive, pro-neurogenic and anti-inflammatory intervention in transgenic mouse models of Alzheimer’s disease

“…The age-related decline in neurogenesis is also accompanied by an age-related decline in cognitive function (Bolognin et al, 2014). Alterations in hippocampal neurogenesis have also been reported in a number of neurodegenerative diseases (AD and Huntington's disease) (Choi et al, 2014a;Moon et al, 2014;Perry et al, 2012), neurological diseases (epilepsy, ischaemia and traumatic brain injury) (D'Alessio et al, 2015;Matsuda et al, 2015;Villasana et al, 2014) and neuropsychiatric conditions (stress and depression) (Boldrini et al, 2012;Lucassen et al, 2015;Miller and Hen, 2015). Deficits in cognitive function have also been reported in some of these conditions.…”

Emerging Roles of Sonic Hedgehog in Adult Neurological Diseases: Neurogenesis and Beyond

“…Neurogenesis is modulated by both physiological stimuli, such as aging factor, exercise, learning, and genetic background [59,60,61,62] as well as pathophysiological conditions, such as seizure [63,64,65] and cerebral ischemia [66,67,68]. Manipulations, especially enhancement, of neurogenesis may carry therapeutic potential that can be applied in brain dysfunction with neuronal injury, such as cerebrovascular diseases and other neurodegenerative disorders.…”

Neurogenesis in Cancun: where science meets the sea

“…Kinichi Nakashima (Kyushu University, Japan) presented data showing how activated microglia can attenuate seizure-induced aberrant adult hippocampal neurogenesis. This beneficial effect of microglia requires DNA-activated TLR9 signaling through MYD88 and TNF-α (Matsuda et al, 2015). As such, TLR9 deletion increases recurrent seizure severity and exacerbates seizure-induced cognitive decline.…”