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 neurotransmission produced by inflammatory mediators. Compared with septic patients, SAE patients had higher
interleukin-1beta (IL-1beta) plasma levels; interestingly, these levels decreased once the
encephalopathy was resolved. A putative IL-1beta effect on type A
gamma-aminobutyric acid receptors (
GABA(A)Rs), 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
GABA(A)Rs, respectively. Confocal images in both cell types revealed that IL-1beta increases recruitment of
GABA(A)Rs to the cell surface. Moreover, brief applications of IL-1beta 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 I(
GABA) recording and confocal images of
GABA(A) Rs in oocytes showed that IL-1beta stimulates the IL-1RI-dependent
phosphatidylinositol 3-kinase activation and the consequent facilitation of phospho-Akt-mediated insertion of
GABA(A)Rs 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-1beta with increased "GABAergic tone." We propose that through this mechanism IL-1beta might alter synaptic strength at central GABAergic synapses and so contribute to the
cognitive dysfunction observed in SAE.