Noninflammatory Changes of Microglia Are Sufficient to Cause Epilepsy

Cell Rep. 2018 Feb 20;22(8):2080-2093. 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.

Keywords: astrocyte; epilepsy; epileptogenesis; inflammation; lysosome; mTOR; microglia; seizure; synapse; tuberous sclerosis complex.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / metabolism
  • Astrocytes / pathology
  • Brain / metabolism
  • Brain / pathology
  • Cell Proliferation
  • Chemokines / metabolism
  • Epilepsy / metabolism
  • Epilepsy / pathology*
  • Female
  • Gene Deletion
  • Inflammation / pathology*
  • Inflammation Mediators / metabolism
  • Lysosomes / metabolism
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microglia / metabolism
  • Microglia / pathology*
  • Phagocytosis
  • Recurrence
  • Signal Transduction
  • Synapses / metabolism
  • TOR Serine-Threonine Kinases / metabolism
  • Tuberous Sclerosis Complex 1 Protein / metabolism


  • Chemokines
  • Inflammation Mediators
  • Tsc1 protein, mouse
  • Tuberous Sclerosis Complex 1 Protein
  • TOR Serine-Threonine Kinases