The pro-inflammatory cytokine interleukin 6 (IL-6) interacts with the central nervous system in a largely unknown manner. We used a genetically modified mouse strain (GFAP-sgp130Fc, TG) and wild type (WT) mice to determine whether IL-6 trans-signaling contributes to basal properties of synaptic transmission. Postsynaptic currents (PSCs) were studied by patch-clamp recording in cortical layer 5 of a mouse prefrontal cortex brain slice preparation. TG and WT animals displayed differences mainly (but not exclusively) in excitatory synaptic responses. The frequency of both action potential-independent (miniature) and action potential-dependent (spontaneous) excitatory PSCs (EPSCs) were higher for TG vs. WT animals. No differences were observed in inhibitory miniature, spontaneous, or tonic inhibitory currents. The pair pulse ratio (PPR) of electrically evoked inhibitory as well as of excitatory PSCs were also larger in TG animals vs. WT ones, while no changes were detected in electrically evoked excitatory-inhibitory synaptic ratio (eEPSC/eIPSC), nor in the ratio between the amino-propionic acid receptor (AMPAR)-mediated and N-methyl D aspartate-R (NMDAR)-mediated components of eEPSCs (I /I ). Evoked IPSC rise times were shorter for TG vs. WT animals. We also compared the sensitivity of TG and WT animals to pentylenetetrazole (PTZ)-induced seizures. We found that TG animals were more sensitive to PTZ injections, as they displayed longer and more severe seizures. We conclude that the absence of basal IL-6 trans-signaling contributes to increase the basal excitability of the central nervous system, at the system level as well at the synaptic level, at least in the prefrontal cortex.