Microglial displacement of inhibitory synapses provides neuroprotection in the adult brain

Nat Commun. 2014 Jul 22;5:4486. doi: 10.1038/ncomms5486.

Abstract

Microglia actively survey the brain microenvironment and play essential roles in sculpting synaptic connections during brain development. While microglial functions in the adult brain are less clear, activated microglia can closely appose neuronal cell bodies and displace axosomatic presynaptic terminals. Microglia-mediated stripping of presynaptic terminals is considered neuroprotective, but the cellular and molecular mechanisms are poorly defined. Using 3D electron microscopy, we demonstrate that activated microglia displace inhibitory presynaptic terminals from cortical neurons in adult mice. Electrophysiological recordings further establish that the reduction in inhibitory GABAergic synapses increased synchronized firing of cortical neurons in γ-frequency band. Increased neuronal activity results in the calcium-mediated activation of CaM kinase IV, phosphorylation of CREB, increased expression of antiapoptotic and neurotrophic molecules and reduced apoptosis of cortical neurons following injury. These results indicate that activated microglia can protect the adult brain by migrating to inhibitory synapses and displacing them from cortical neurons.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Brain / drug effects
  • Brain / pathology
  • Brain / physiology*
  • Calcium-Calmodulin-Dependent Protein Kinase Type 4 / metabolism
  • Cerebral Cortex / metabolism
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Electrophysiology / methods
  • Imaging, Three-Dimensional
  • Lipopolysaccharides / pharmacology
  • Male
  • Mice, Inbred C57BL
  • Microglia / drug effects
  • Microglia / physiology*
  • Microscopy, Electron
  • Neurons / metabolism
  • Phosphorylation
  • Presynaptic Terminals / metabolism
  • Rats, Sprague-Dawley
  • Synapses / drug effects
  • Synapses / metabolism
  • Synapses / physiology*
  • gamma-Aminobutyric Acid / metabolism

Substances

  • Creb1 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • Lipopolysaccharides
  • gamma-Aminobutyric Acid
  • Calcium-Calmodulin-Dependent Protein Kinase Type 4