Microglial TLR9: Guardians of Homeostatic Hippocampal Neurogenesis

Commentary Epileptogenesis is a multifaceted process in which various cellular components contribute to the development of epilepsy. Among them, aberrant hippocampal neurogenesis induced by acute seizures is thought to be among the crucial players in the generation of spontaneous recurrent seizures and memory impairment (1, 2). However, the cellular and molecular mechanisms that regulate seizure-induced aberrant neurogenesis in the hippocampus remain largely unknown. In this study, Matsuda et al. elegantly showed that microglial activation after kainic acid (KA)-induced seizures could affect chronic seizure susceptibility and memory function by modulating the proliferation of hippocampal neural progenitors. With genetic and pharmacological manipulation of microglial activation, in addition to a conditioned medium-based cell culture system, the authors demonstrated microglial mechanisms controlling seizure-induced aberrant hippocampal neurogenesis. In their study, self-DNAs—possibly derived from nearby dead or degenerating neurons—could stimulate microglial Toll-like receptor 9 (TLR9), which triggered TNF-α production via the NF-κB signaling pathway, resulting in the reduced proliferation of neural progenitor cells in the epileptic dentate gyrus. Microglia (resident immune cells in the brain) have long been considered to play deleterious roles in epileptogenesis (3). Activated by various brain insults, microglia produce and secrete proinflammatory cytokines such as interleukin-1 (IL-1) and TNF-α. This cytokine surge turns on downstream signaling cascades, leading to histopathological outcomes and functional impairment. However, other studies have suggested that microglia have positive roles in epilepsy by secreting antiinflammatory cytokines, including IL-4, IL-10, and TGF-β. The paper discussed here supports the beneficial side of microglia. For example, both inhibition of microglial activation using minocycline or suppression of TNF-α by thalidomide aggravated seizure-induced enhanced proliferation in the dentate gyrus. Interestingly, considering that minocycline is an inhibitor of proinflammatory cytokine-producing microglia, the authors suggest a novel mechanism of proinflammatory microglia affecting epileptogenesis and a new positive effect of microglia in epilepsy. Since microglia can display proand anti-inflammatory functional states—depending on the different combinations of inducing factors, which largely fluctuates during the course of epileptogenesis—it will be interesting to further investigate the temporal pattern of alternating microglial states and their specific roles in aberrant hippocampal neurogenesis. TLRs are pattern-recognition receptors that respond to pathogen-associated molecular patterns (PAMPs) or damageassociated molecular patterns (DAMPs). Ever since the first human TLR was identified (4), many additional TLRs have been extensively studied in the brain. In adult hippocampus, TLR4 deficiency was shown to induce the proliferation of hippocampal progenitor cells (5). Moreover, TLRs are involved in cell fate choice. For example, TLR2 deletion promotes astrocyte differentiation at the expense of neurogenesis, while TLR4 deficiency promotes neuronal differentiation without affecting astrocyte differentiation (5). As expected, TLRs can also affect the survival of newborn granule cells, given that TLR3-deficient mice showed an increased number of adult-generated mature neurons (6). As for TLR9, the authors found no difference in the TLR9 Signalling in Microglia Attenuates Seizure-Induced Aberrant Neurogenesis in the Adult Hippocampus.