Neuronal Hyperactivity Recruits Microglial Processes via Neuronal NMDA Receptors and Microglial P2Y12 Receptors After Status Epilepticus

J Neurosci. 2014 Aug 6;34(32):10528-40. doi: 10.1523/JNEUROSCI.0416-14.2014.

Abstract

Microglia are highly dynamic immune cells of the CNS and their dynamism is proposed to be regulated by neuronal activities. However, the mechanisms underlying neuronal regulation of microglial dynamism have not been determined. Here, we found an increased number of microglial primary processes in the hippocampus during KA-induced seizure activity. Consistently, global glutamate induced robust microglial process extension toward neurons in both brain slices and in the intact brain in vivo. The mechanism of the glutamate-induced microglial process extension involves the activation of neuronal NMDA receptors, calcium influx, subsequent ATP release, and microglial response through P2Y12 receptors. Seizure-induced increases in microglial process numbers were also dependent on NMDA receptor activation. Finally, we found that P2Y12 KO mice exhibited reduced seizure-induced increases in microglial process numbers and worsened KA-induced seizure behaviors. Our results elucidate the molecular mechanisms underlying microglia-neuron communication that may be potentially neuroprotective in the epileptic brain.

Keywords: NMDA receptor; P2Y12 receptor; epilepsy; glutamate; microglia; process extension.

Publication types

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

MeSH terms

  • Animals
  • CX3C Chemokine Receptor 1
  • Cell Surface Extensions / drug effects
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Excitatory Amino Acid Agents / pharmacology
  • Female
  • Hippocampus / pathology*
  • In Vitro Techniques
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Male
  • Mice
  • Mice, Transgenic
  • Microglia / cytology
  • Microglia / physiology*
  • Neurons / drug effects
  • Neurons / physiology*
  • Potassium Chloride / pharmacology
  • Receptors, Chemokine / genetics
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Receptors, Purinergic P2Y12 / deficiency
  • Receptors, Purinergic P2Y12 / metabolism*
  • Sodium Channel Blockers / pharmacology
  • Status Epilepticus / chemically induced
  • Status Epilepticus / genetics
  • Status Epilepticus / pathology*

Substances

  • CX3C Chemokine Receptor 1
  • Cx3cr1 protein, mouse
  • Excitatory Amino Acid Agents
  • Luminescent Proteins
  • P2ry12 protein, mouse
  • Receptors, Chemokine
  • Receptors, N-Methyl-D-Aspartate
  • Receptors, Purinergic P2Y12
  • Sodium Channel Blockers
  • Potassium Chloride