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.

Nicotine is the major addictive component of cigarettes, reaching a brain concentration of ~300 nM during smoking of a single cigarette. The prefrontal cortex (PFC) mechanisms underlying temporary changes of working memory during smoking are incompletely understood. Here, we investigated whether 300 nM nicotine modulates γ‐aminobutyric acid (GABA) ergic synaptic transmission from pyramidal neurons of the output layer (V) of the murine medial PFC. We used patch clamp in vitro recording from C57BL/6 mice in the whole‐cell configuration to investigate the effect of nicotine on pharmacologically isolated GABAergic postsynaptic currents (IPSCs) in the absence or presence of methyllycaconitine (MLA) or dihydro‐β‐erythroidine (DHβE), selective antagonists of α7‐ and β2‐containing (α7* and β2*) nicotinic acetylcholine receptors (AChRs), respectively. Our results indicated that nicotine, alone or in the presence of MLA, decreases electrically evoked IPSC (eIPSC) amplitude, whereas in the presence of DHβE, nicotine elicited either an eIPSCs amplitude increase or a decrease. In the presence of DHβE, nicotine increased membrane conductance leaving the paired pulse ratio unchanged in all conditions, suggesting a non‐β2* mediated effect. In the presence of MLA, nicotine decreased the mean spontaneous IPSC (sIPSC) frequency but increased their rise time, suggesting a non‐α7* AChR‐mediated synaptic modulation. Also, in the presence of DHβE, nicotine decreased both eIPSC rise and decay times. No receptors other than α7* and β2* appear to be involved in the nicotine effect. Our results indicate that nicotine smoking concentrations modulate GABAergic synaptic currents through mixed pre‐ and post‐synaptic mechanisms by activation of α7* and β2* AChRs.

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