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 language | English |
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Pages (from-to) | 574-582 |
Number of pages | 9 |
Journal | Biological Psychiatry |
Volume | 71 |
Issue number | 7 |
DOIs | |
State | Published - 1 Apr 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)