Noninflammatory Changes of Microglia Are Sufficient to Cause Epilepsy

• Published in: Cell reports (Cambridge) 2018-02, Vol.22 (8), p.2080-2093
• Main Authors: Zhao, Xiaofeng, Liao, Yuan, Morgan, Shannon, Mathur, Ramkumar, Feustel, Paul, Mazurkiewicz, Joseph, Qian, Jiang, Chang, Julia, Mathern, Gary W., Adamo, Matthew A., Ritaccio, Anthony L., Gruenthal, Michael, Zhu, Xinjun, Huang, Yunfei
• Format: Article
• Language: English
• Subjects: Animals; astrocyte; Astrocytes - metabolism; Astrocytes - pathology; Brain - metabolism; Brain - pathology; Cell Proliferation; Chemokines - metabolism; epilepsy; Epilepsy - metabolism; Epilepsy - pathology; epileptogenesis; Female; Gene Deletion; inflammation; Inflammation - pathology; Inflammation Mediators - metabolism; lysosome; Lysosomes - metabolism; Male; Mice, Inbred C57BL; Mice, Knockout; microglia; Microglia - metabolism; Microglia - pathology; mTOR; Phagocytosis; Recurrence; seizure; Signal Transduction; synapse; Synapses - metabolism; TOR Serine-Threonine Kinases - metabolism; tuberous sclerosis complex; Tuberous Sclerosis Complex 1 Protein - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2018.02.004

Microglia are well known to play a critical role in maintaining brain homeostasis. However, their role in epileptogenesis has yet to be determined. Here, we demonstrate that elevated mTOR signaling in mouse microglia leads to phenotypic changes, including an amoeboid-like morphology, increased proliferation, and robust phagocytosis activity, but without a significant induction of pro-inflammatory cytokines. We further provide evidence that these noninflammatory changes in microglia disrupt homeostasis of the CNS, leading to reduced synapse density, marked microglial infiltration into hippocampal pyramidal layers, moderate neuronal degeneration, and massive proliferation of astrocytes. Moreover, the mice thus affected develop severe early-onset spontaneous recurrent seizures (SRSs). Therefore, we have revealed an epileptogenic mechanism that is independent of the microglial inflammatory response. Our data suggest that microglia could be an opportune target for epilepsy prevention. [Display omitted] •Microglia adopt a noninflammatory reactive-like phenotype upon mTOR activation•Elevation of microglial mTOR activity triggers marked proliferation of astrocytes•Reactive-like microglia drive epileptogenesis independent of inflammatory responses Zhao et al. reveal that elevated mTOR signaling in microglia propels the cells to acquire a noninflammatory reactive-like phenotype, which leads to disruption of CNS homeostasis. The authors also report that reactive-like microglia promote epileptogenesis independent of the inflammatory response.