Postnatal activation of TLR4 in astrocytes promotes excitatory synaptogenesis in hippocampal neurons

J Cell Biol. 2016 Dec 5;215(5):719-734. doi: 10.1083/jcb.201605046. Epub 2016 Nov 10.


Astrocytes are critical in synapse development, and their dysfunction in crucial developmental stages leads to serious neurodevelopmental diseases, including seizures and epilepsy. Immune challenges not only affect brain development, but also promote seizure generation and epileptogenesis, implying immune activation is one of the key factors linking seizures and epilepsy to abnormal brain development. In this study, we report that activating astrocytes by systemic lipopolysaccharide (LPS) challenges in the second postnatal week promotes excitatory synapse development, leading to enhanced seizure susceptibility in mice. Toll-like receptor 4 (TLR4) activation in astrocytes increased astrocytic extracellular signal-related kinase 1/2 (Erk1/2) and phospho-Erk1/2 levels in a myeloid differentiation primary response protein 88 (MyD88)-dependent manner. Constitutively activating Erk1/2 in astrocytes was sufficient to enhance excitatory synaptogenesis without activating TLR4. Deleting MyD88 or suppressing Erk1/2 in astrocytes rescued LPS-induced developmental abnormalities of excitatory synapses and restored the enhanced seizure sensitivity. Thus, we provide direct evidence for a developmental role of astrocytes in shaping a predisposition to seizure generation.

MeSH terms

  • Animals
  • Animals, Newborn
  • Astrocytes / metabolism*
  • Coculture Techniques
  • Dendrites / metabolism
  • Disease Susceptibility
  • Enzyme Activation
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Hippocampus / pathology*
  • Lipopolysaccharides
  • Mice
  • Mice, Inbred C57BL
  • Myeloid Differentiation Factor 88 / metabolism
  • Neurogenesis*
  • Neurons / metabolism*
  • Pentylenetetrazole
  • Pyramidal Cells / metabolism
  • Seizures / pathology
  • Signal Transduction
  • Synapses / metabolism*
  • Synaptic Transmission
  • Toll-Like Receptor 4 / metabolism*


  • Lipopolysaccharides
  • Myeloid Differentiation Factor 88
  • Toll-Like Receptor 4
  • Extracellular Signal-Regulated MAP Kinases
  • Pentylenetetrazole