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Two-photon Imaging of Microglial Processes' Attraction Toward ATP or Serotonin in Acute Brain Slices
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Two-photon Imaging of Microglial Processes' Attraction Toward ATP or Serotonin in Acute Brain Slices

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Activation of neuronal NMDA receptors triggers transient ATP-mediated microglial process outgrowth

Lasse Dissing-Olesen1, Jeffrey M LeDue1, Ravi L Rungta1

  • 1Brain Research Centre, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada.

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
|August 8, 2014
PubMed

Insights

Neuronal NMDA receptor activation triggers ATP release, a novel signaling molecule, which stimulates microglia process outgrowth. This discovery reveals a new pathway for neuron-microglia communication.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Neuroimmunology

Background:

  • Microglia, the brain's immune cells, exhibit dynamic morphology and respond to stimuli like extracellular ATP.
  • Neuronal activity is known to influence microglial behavior, but the precise mechanisms remain incompletely understood.

Purpose of the Study:

  • To investigate if stimulating neuronal N-methyl-D-aspartate receptors (NMDARs) triggers ATP release, thereby mediating communication with microglia.
  • To elucidate the signaling pathways involved in NMDA-induced microglial process extension.

Main Methods:

  • Utilized acute mouse hippocampal brain slices and two-photon laser scanning microscopy to observe microglial dynamics.
  • Developed a novel protocol for microglia process fixation and immunolabeling.
  • Employed pharmacological antagonists for NMDARs, AMPA/kainate receptors, and voltage-gated sodium channels.
  • Investigated the role of purinergic receptors, ATP hydrolysis, Pannexin 1, connexins, and nitric oxide.

Main Results:

  • NMDA stimulation induced transient, reversible, and repeatable microglia process outgrowth, distinct from excitotoxic damage.
  • NMDAR stimulation was essential, as antagonists blocked the outgrowth, while other receptor blockers did not.
  • ATP release secondary to NMDAR activation was identified as the key mediator, with purinergic receptor blockade or inhibited ATP hydrolysis abolishing outgrowth.
  • Microglia response was independent of Pannexin 1, astrocyte connexins, and nitric oxide.
  • Activation of dendritic NMDARs on single neurons was sufficient to trigger microglia process outgrowth.

Conclusions:

  • Dendritic neuronal NMDAR activation initiates a novel form of neuron-microglial communication.
  • This communication is mediated by ATP release through a Pannexin 1-independent pathway.
  • The findings reveal an uncharacterized mechanism of ATP-driven signaling between neurons and microglia.
Keywords:
ATP purinergic receptorsNMDA glutamate receptorsPannexinmicroglia process motilitysynaptic surveillance

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