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 intraventricular 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.

Acute systemic LPS-mediated inflammation induces lasting changes in mouse cortical neuromodulation and behavior

“…We employ bolus application of neuromodulators upstream of the recording electrode in the slice perfusate to simulate phasic release of neuromodulators known to be associated with salient environmental stimuli that are necessary for transient modulation of executive functions [13,22]. Our results show that systemic LPS injection, not only reduces cortical inhibition, consistent with prior studies [7,17,20], but also alters the temporal dynamics of ACh-neuromodulation that is associated with increased ACh-E activity and impairment in memory performance. Although AChneuromodulation is affected, NE and 5-HT effects were not altered, consistent with the lack of a behavioral effect on anxiety and despair assessments.…”

“…The acute prostaglandin-mediated behavioral response typically subsides within 2-3 days [8] while systemic inflammation subsides within 7-10 days [16]. However, inflammatory cytokine-mediated increases in brain excitation [7,20] may be much longer-lasting. Additionally, inflammatory signaling pathways, reactive oxygen species and stress are all known to increase monoamine oxidase-A (MAO-A) and acetylcholinesterase (ACh-E) activity in vitro [4,11,14].…”

Neuroimmune mechanisms of depression

“…Intracranial infusions of IL-6 91 or administration of IL-1b 92, 93 into the hippocampus increase depression associated behavior and reduces neurogenesis, whereas infusion of IL-1b 93 and IL-6 91 antibodies, or genetic deletion of IL-6 94 , blocks the depressive-like effects induced by CMS. Cytokines can act on serotonin neurons through the kynurenine pathway and tryptophan catabolites 95, 96 as well as directly on glutamatergic neurons in the frontal cortex 97 and hippocampus 98 to alter synaptic plasticity. Danger signals also act directly on nerve cells that express the TLR4 receptor to alter neurogenesis in the hippocampus 99 , a process important for depression and antidepressant responses 100 Lastly, cytokines/chemokines can activate a microglia-dependent phagocytic process that engulfs and clears excitatory synapses altering synaptic transmission and behavior 101 .…”

Theiler's murine encephalomyelitis virus infection of SJL/J and C57BL/6J mice: Models for multiple sclerosis and epilepsy

“…In a study by Levy et al, mice treated with intraventricular injections of IL-6 were monitored for cortical seizure activity and they displayed significantly more seizure-like activity when compared to control mice (Levy et al, 2015). Single cell recordings performed in cortical rat slice preparations have shown that IL-6 application causes a decrease in evoked inhibitory post synaptic current amplitude without changing evoked excitatory post synaptic current amplitudes (Garcia-Oscos et al, 2012); suggesting IL-6 can drive neurons into a more excitable state. Moreover, transgenic mice with increased astrocytic production of IL-6 driven by GFAP (GFAP-IL6) have been found to be significantly more sensitive to NMDA- and KA-induced seizures (Campbell et al, 1993; Samland et al, 2003).…”