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 to septic patients, SAE patients had higher interleukin-1 (IL-1) plasma levels; interestingly, these levels decreased once the encephalopathy was resolved. A putative IL-1 effect on type-A GABA receptors (GABA_ARs), 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_ARs, respectively. Confocal images in both cell types reveal that IL-1increases recruitment of GABA_ARs to the cell surface. Moreover, brief applications of IL-1 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_ARs in oocytes show that IL-1 stimulates the IL-1RI-dependent phosphatidylinositol 3-kinase (PI3-K) activation and the consequent facilitation of phospho-Akt-mediated insertion of GABAARs into the cell surface. The interruption of this signaling pathway by specific PI3-K or Akt inhibitors suppresses the cytokine-mediated effects on GABAAR 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 with increased “GABAergic tone”. We propose that, through this mechanism, IL-1 might alter synaptic strength at central GABAergic synapses and so contribute to the cognitive dysfunction observed in SAE.