Interleukin-1β enhances GABAA receptor cell-surface expression by a phosphatidylinositol 3-kinase/Akt pathway -: Relevance to sepsis-associated encephalopathy

Sepsis-associated encephalopathy (SAE) is a frequent but poorly understood neurological complication in sepsis that negatively influences survival. Here we present clinical and experimental evidence that this brain dysfunction may be related to altered neuro-transmission produced by inflammatory mediators. Compared with septic patients, SAE patients had higher interleukin-1 beta (IL-1 beta) plasma levels; interestingly, these levels decreased once the encephalopathy was resolved. A putative IL-1 beta effect on type A gamma-aminobutyric acid receptors (GABAARs), which mediate fast synaptic transmission in most cerebral inhibitory synapses in mammals, was investigated in cultured hippocampal neurons and in Xenopus oocytes expressing native or foreign rat brain GABAARs, respectively. Confocal images in both cell types revealed that IL-1 beta increases recruitment of GABAARs to the cell surface. Moreover, brief applications of IL-1 beta to voltage-clamped oocytes yielded a delayed potentiation of the GABA-elicited chloride currents (I-GABA); this effect was suppressed by IL-1ra, the natural IL- 1 receptor (IL-1RI) antagonist. Western blot analysis combined with IGABA recording and confocal images of GABAARs in oocytes showed that IL-1 beta stimulates the IL-1RI-dependent phosphatidylinositol 3- kinase activation and the consequent facilitation of phospho-Akt-mediated insertion of GABAARs into the cell surface. The interruption of this signaling pathway by specific phosphatidylinositol 3- kinase or Akt inhibitors suppresses the cytokine-mediated effects on GABA(A)R, whereas activation of the conditionally active form of Akt1 (myr-Akt1.ER*) with 4-hydroxytamoxifen reproduces the effects. These findings point to a previously unrecognized signaling pathway that connects IL-1 beta with increased GABAergic tone. We propose that through this mechanism IL-1 beta might alter synaptic strength at central GABAergic synapses and so contribute to the cognitive dysfunction observed in SAE.