Neuroinflammation Alters Integrative Properties of Rat Hippocampal Pyramidal Cells

Mol Neurobiol. 2018 Sep;55(9):7500-7511. doi: 10.1007/s12035-018-0915-1. Epub 2018 Feb 9.


Neuroinflammation is consistently found in many neurological disorders, but whether or not the inflammatory response independently affects neuronal network properties is poorly understood. Here, we report that intracerebroventricular injection of the prototypical inflammatory molecule lipopolysaccharide (LPS) in rats triggered a strong and long-lasting inflammatory response in hippocampal microglia associated with a concomitant upregulation of Toll-like receptor (TLR4) in pyramidal and hilar neurons. This, in turn, was associated with a significant reduction of the dendritic hyperpolarization-activated cyclic AMP-gated channel type 1 (HCN1) protein level while Kv4.2 channels were unaltered as assessed by western blot. Immunohistochemistry confirmed the HCN1 decrease in CA1 pyramidal neurons and showed that these changes were associated with a reduction of TRIP8b, an auxiliary subunit for HCN channels implicated in channel subcellular localization and trafficking. At the physiological level, this effect translated into a 50% decrease in HCN1-mediated currents (Ih) measured in the distal dendrites of hippocampal CA1 pyramidal cells. At the functional level, the band-pass-filtering properties of dendrites in the theta frequency range (4-12 Hz) and their temporal summation properties were compromised. We conclude that neuroinflammation can independently trigger an acquired channelopathy in CA1 pyramidal cell dendrites that alters their integrative properties. By directly changing cellular function, this phenomenon may participate in the phenotypic expression of various brain diseases.

Keywords: Brain disease; Channelopathy; Cytokines; HCN1; HMGB1; Rat; lipopolysaccharide.

MeSH terms

  • Animals
  • Dendrites / metabolism
  • Down-Regulation
  • Hippocampus / pathology*
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / metabolism
  • Inflammation / pathology*
  • Lipopolysaccharides
  • Male
  • Membrane Proteins / metabolism
  • Microglia / metabolism
  • Microglia / pathology
  • Potassium Channels / metabolism
  • Pyramidal Cells / metabolism
  • Pyramidal Cells / pathology*
  • Rats, Sprague-Dawley
  • Time Factors
  • Toll-Like Receptor 4 / metabolism


  • Hcn1 protein, rat
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Lipopolysaccharides
  • Membrane Proteins
  • Pex5l protein, rat
  • Potassium Channels
  • Toll-Like Receptor 4