The stress-induced cytokine interleukin-6 decreases the inhibition/excitation ratio in the rat temporal cortex via trans-signaling

Francisco Garcia-Oscos, Humberto Salgado, Shawn Hall, Feba Thomas, George E. Farmer, Jorge Bermeo, Luis Charles Galindo, Ruben D. Ramirez, Santosh D'Mello, Stefan Rose-John, Marco Atzori

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Abstract

Background: Although it is known that stress elevates the levels of pro-inflammatory cytokines and promotes hyper-excitable central conditions, a causal relationship between these two factors has not yet been identified. Recent studies suggest that increases in interleukin 6 (IL-6) levels are specifically associated with stress. We hypothesized that IL-6 acutely and directly induces cortical hyper-excitability by altering the balance between synaptic excitation and inhibition. Methods: We used patch-clamp to determine the effects of exogenous or endogenous IL-6 on electrically evoked postsynaptic currents on a cortical rat slice preparation. We used control subjects or animals systemically injected with lipopolysaccharide or subjected to electrical foot-shock as rat models of stress. Results: In control animals, IL-6 did not affect excitatory postsynaptic currents but selectively and reversibly reduced the amplitude of inhibitory postsynaptic currents with a postsynaptic effect. The IL-6-induced inhibitory postsynaptic currents decrease was inhibited by drugs interfering with receptor trafficking and/or internalization, including wortmannin, Brefeldin A, 2-Br-hexadecanoic acid, or dynamin peptide inhibitor. In both animal models, stress-induced decrease in synaptic inhibition/excitation ratio was prevented by prior intra-ventricular injection of an analog of the endogenous IL-6 trans-signaling blocker gp130. Conclusions: Our results suggest that stress-induced IL-6 shifts the balance between synaptic inhibition and excitation in favor of the latter, possibly by decreasing the density of functional γ-aminobutyric acid A receptors, accelerating their removal and/or decreasing their insertion rate from/to the plasma membrane. We speculate that this mechanism could contribute to stress-induced detrimental long-term increases in central excitability present in a variety of neurological and psychiatric conditions.

Original languageEnglish (US)
Pages (from-to)574-582
Number of pages9
JournalBiological Psychiatry
Volume71
Issue number7
DOIs
StatePublished - Apr 1 2012

Keywords

  • 2-Br-hexadecanoic acid
  • Brefeldin A
  • PI3K/AKT
  • dynamin inhibitory peptide
  • foot-shock
  • gp130
  • interleukin-6 (IL-6)
  • lipopolysaccharide (LPS)
  • patch-clamp
  • postsynaptic
  • rat
  • stress
  • temporal cortex
  • trans-signaling
  • wortmannin
  • γ-aminobutyric acid (GABA)

ASJC Scopus subject areas

  • Biological Psychiatry

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    Garcia-Oscos, F., Salgado, H., Hall, S., Thomas, F., Farmer, G. E., Bermeo, J., Galindo, L. C., Ramirez, R. D., D'Mello, S., Rose-John, S., & Atzori, M. (2012). The stress-induced cytokine interleukin-6 decreases the inhibition/excitation ratio in the rat temporal cortex via trans-signaling. Biological Psychiatry, 71(7), 574-582. https://doi.org/10.1016/j.biopsych.2011.11.018