title: The stress-induced cytokine interleukin-6 decreases the inhibition/excitation ratio in the rat temporal cortex via trans-signaling.
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.
authors.affiliation: School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, 75080, USA.
authors.forename: Francisco
authors.initials: F
authors.lastname: Garcia-Oscos
authors.forename: Humberto
authors.initials: H
authors.lastname: Salgado
authors.forename: Shawn
authors.initials: S
authors.lastname: Hall
authors.forename: Feba
authors.initials: F
authors.lastname: Thomas
authors.forename: George E
authors.initials: GE
authors.lastname: Farmer
authors.forename: Jorge
authors.initials: J
authors.lastname: Bermeo
authors.forename: Luis Charles
authors.initials: LC
authors.lastname: Galindo
authors.forename: Ruben D
authors.initials: RD
authors.lastname: Ramirez
authors.forename: Santosh
authors.initials: S
authors.lastname: D'Mello
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.forename: Marco
authors.initials: M
authors.lastname: Atzori
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D020126:Brefeldin A / Q000494:pharmacology; D050822:Cytokine Receptor gp130 / Q000037:antagonists & inhibitors; D004195:Disease Models, Animal; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D015850:Interleukin-6 / Q000494:pharmacology / Q000502:physiology*; D008070:Lipopolysaccharides; D009118:Muscimol / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010168:Palmitates / Q000494:pharmacology; D051381:Rats; D013315:Stress, Psychological / Q000139:chemically induced / Q000503:physiopathology*; D013702:Temporal Lobe / Q000187:drug effects / Q000503:physiopathology*; D000077191:Wortmannin; D000093242:Interleukin-6 Inhibitors
chemical_list: D000730:Androstadienes; D020126:Brefeldin A; D050822:Cytokine Receptor gp130; D015850:Interleukin-6; D008070:Lipopolysaccharides; D009118:Muscimol; D009842:Oligopeptides; D010168:Palmitates; D000077191:Wortmannin; D000093242:Interleukin-6 Inhibitors; C560821:peptide P4; C022776:2-bromopalmitate