Microglia shape presynaptic properties at developing glutamatergic synapses

Glia. 2019 Jan;67(1):53-67. doi: 10.1002/glia.23508. Epub 2018 Nov 11.


Deficient neuron-microglia signaling during brain development is associated with abnormal synaptic maturation. However, the precise impact of deficient microglia function on synaptic maturation and the mechanisms involved remain poorly defined. Here we report that mice defective in neuron-to-microglia signaling via the fractalkine receptor (Cx3cr1 KO) show reduced microglial branching and altered motility and develop widespread deficits in glutamatergic neurotransmission. We characterized the functional properties of CA3-CA1 synapses in hippocampal slices from these mice and found that they display altered glutamatergic release probability, maintaining immature properties also at late developmental stages. In particular, CA1 synapses of Cx3cr1 KO show (i) immature AMPA/NMDA ratio across developmental time, displaying a normal NMDA component and a defective AMPA component of EPSC; (ii) defective functional connectivity, as demonstrated by reduced current amplitudes in the input/output curve; and (iii) greater facilitation in the paired pulse ratio (PPR), suggesting decreased release probability. In addition, minimal stimulation experiments revealed that excitatory synapses have normal potency, but an increased number of failures, confirming a deficit in presynaptic release. Consistently, KO mice were characterized by higher number of silent synapses in comparison to WT. The presynaptic deficits were corrected by performing experiments in conditions of high release probability (Ca2+ /Mg2+ ratio 8), where excitatory synapses showed normal synaptic multiplicity, AMPA/NMDA ratio, and proportion of silent synapses. These results establish that neuron-microglia interactions profoundly influence the functional maturation of excitatory presynaptic function.

Keywords: CX3CR1; hippocampus; microglia; neuron-microglia interaction; synaptic development; synaptic transmission.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Excitatory Postsynaptic Potentials
  • Glutamic Acid / physiology*
  • Hippocampus / cytology
  • Hippocampus / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microglia / physiology*
  • Neurons / physiology*
  • Organ Culture Techniques
  • Presynaptic Terminals / physiology*
  • Synapses / physiology*


  • Glutamic Acid