Molecular Neurobiology

, Volume 55, Issue 9, pp 7500–7511 | Cite as

Neuroinflammation Alters Integrative Properties of Rat Hippocampal Pyramidal Cells

  • Federica Frigerio
  • Corey Flynn
  • Ye Han
  • Kyle Lyman
  • Joaquin N. Lugo
  • Teresa Ravizza
  • Antoine Ghestem
  • Julika Pitsch
  • Albert Becker
  • Anne E. Anderson
  • Annamaria VezzaniEmail author
  • Dane Chetkovich
  • Christophe BernardEmail author


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.


Cytokines HMGB1 HCN1 Channelopathy lipopolysaccharide Rat Brain disease 



We thank Amy L. Brewster and Francesco Noé for their contribution to the initial experiments.

Funding Information

This work was supported by INSERM, ANR MINOS, and ANTARES (C.B.), and the European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement n°602102 (EPITARGET to C.B. and A.V.), C.F. was supported by an Alberta Heritage Foundation for Medical Research (AHFMR) Fellowship. Additionally, this work was supported by Fondazione Italo Monzino (A.V.), National Institutes of Health Grant 2R01NS059934, R01MH106511, and R21MH104471 (D.M.C).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12035_2018_915_Fig5_ESM.gif (123 kb)
Fig. S1

IL-1β expressing microglia in the rat hippocampus after LPS. ad Representative photomicrographs showing the progressive changes in IL-1β immunoreactivity in the rat septal hippocampus at various times (n = 4–12 rats) after bilateral icv LPS injection (25 μg/2 μl) vs vehicle injection (n = 2–8 rats). Six hours after LPS injection (b), IL-1β immunostaining was increased in the hippocampal regions adjacent to the ventricular area. IL-1β signal was strongly induced throughout the whole hippocampus at 24 h (c) post-LPS, then declining by 1 week (d) to undetectable levels as in sham controls (a). The merge images (e, f) show co-localization of IL-1β signal with the microglia marker OX-42 (yellow signal in e) but not with the astrocytic marker GFAP (f). Bargram in (g) depicts the quantification of IL-1β expression 24 h post-LPS (area occupied by the specific signal/total area analyzed). CA1, CA3 pyramidal cell layers, h hilus. Scale bar: ad, 220 μm; e, f 25 μm (GIF 123 kb)

12035_2018_915_MOESM1_ESM.tif (6.7 mb)
High-Resolution Image (TIFF 6811 kb)
12035_2018_915_Fig6_ESM.gif (91 kb)
Fig. S2

Treatment with LPS causes a reduction in total hippocampal HCN1 protein but not TRIP8b. Western blots were performed from whole hippocampi of rats treated with either vehicle or LPS (n = 5 each experimental group). A significant reduction in HCN1 (a, b) was observed without a difference in TRIP8b (c, d). Data are mean ± s.e.m. *p < 0.05 by Mann–Whitney test (GIF 91 kb)

12035_2018_915_MOESM2_ESM.tif (729 kb)
High-Resolution Image (TIFF 728 kb)
12035_2018_915_Fig7_ESM.gif (87 kb)
Fig S3

Blockade of LPS effects by the selective TLR4 antagonist Cyanobacterial LPS. Rats were injected icv with Cyanobacterial LPS (CyP; 60 μg/3 μl in PBS, bilaterally) 15 min before and 15 min after icv LPS injection (25 μg/2 μl in PBS bilaterally). Rats were sacrificed 24 h after LPS injection. a A significant reduction of IL-1β staining was observed by immunohistochemistry in rats treated with LPS + CyP vs LPS alone (n = 5 rats each group). CA1, CA1 pyramidal neurons, CA3, CA3 pyramidal neurons, h hilus. Scale bar 250 μm. b LPS-induced reduction of HCN1 was prevented by CyP as assessed by western blot. Data are mean ± s.e.m. (n = 8–9 rats). *p < 0.05 by Kruskal-Wallis followed by Dunn’s post-hoc test (GIF 86 kb)

12035_2018_915_MOESM3_ESM.tif (368 kb)
High-Resolution Image (TIFF 367 kb)


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Federica Frigerio
    • 1
  • Corey Flynn
    • 2
  • Ye Han
    • 3
  • Kyle Lyman
    • 3
  • Joaquin N. Lugo
    • 4
  • Teresa Ravizza
    • 1
  • Antoine Ghestem
    • 2
  • Julika Pitsch
    • 5
  • Albert Becker
    • 5
  • Anne E. Anderson
    • 6
  • Annamaria Vezzani
    • 1
    Email author
  • Dane Chetkovich
    • 3
    • 7
  • Christophe Bernard
    • 2
    Email author
  1. 1.Department of NeuroscienceIRCCS-Mario Negri Institute for Pharmacological ResearchMilanItaly
  2. 2.INSERM U1106, INS, Institut de Neurosciences des SystèmesAix-Marseille UniversitéMarseilleFrance
  3. 3.Davee Department of Neurology and Clinical NeurosciencesNorthwestern University Feinberg School of MedicineChicagoUSA
  4. 4.Department of Psychology and Neuroscience, Institute of Biomedical StudiesBaylor UniversityWacoUSA
  5. 5.Section for Translational Epilepsy Research, Department of NeuropathologyUniversity of Bonn Medical CenterBonnGermany
  6. 6.Departments of Pediatrics, Neurology and NeuroscienceBaylor College of MedicineHoustonUSA
  7. 7.Vanderbilt University Medical CenterNashvilleUSA

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