Nicotine smoking concentrations modulate GABAergic synaptic transmission in murine medial prefrontal cortex by activation of α7* and ß2* nicotinic receptors.

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-ß-erythroidine (DHßE), selective antagonists of α7- and ß2-containing (α7* and ß2*) 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 DHßE, nicotine elicited either an eIPSCs amplitude increase or a decrease. In the presence of DHßE, nicotine increased membrane conductance leaving the paired pulse ratio unchanged in all conditions, suggesting a non-ß2* 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 DHßE, nicotine decreased both eIPSC rise and decay times. No receptors other than α7* and ß2* 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 ß2* AChRs.

Interleukin 6 trans-signaling regulates basal synaptic transmission and sensitivity to pentylenetetrazole-induced seizures in mice.

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 (IAMPA /INMDA ). 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.

Interleukin 6 Dependent Synaptic Plasticity in a Social Defeat-Susceptible Prefrontal Cortex Circuit.

The role of the pro-inflammatory cytokine interleukin-6 (IL-6) in the etiology of stress-induced synaptic plasticity is yet unknown. We took advantage of a genetically modified mouse (TG) in which IL-6 trans-signaling via the soluble IL-6 receptor was blocked, to determine the role of IL-6 trans-signaling in the effects of a Social Defeat protocol (SD) on synaptic function of the medial prefrontal cortex (mPFC). Synaptic function in stress-sensitive (S) and stress-resilient (R) animals was studied in a mPFC slice preparation with whole-cell patch-clamp recording. SD altered numerous synaptic properties of the mPFC: R WT (but not TG) displayed a decreased ratio between N methyl-D-aspartate receptor (NMDAR-) dependent and amino propionic acid receptor (AMPAR-) dependent-current (INMDA/IAMPA), while S WT animals (but not TG) showed a reduced ratio between AMPA and γ-amino-butyric acid receptor type A (GABAAR)-dependent currents (IAMPA/IGABA). Also, SD induced an increase in the frequency but a decrease in the amplitude of excitatory action-potential dependent PSCs (sEPSCs), both in an IL-6 dependent manner, as well as a generalized (S/R-independent) decrease in the frequency of action potential independent (miniature) excitatory (IL-6 dependent) as well as inhibitory (IL-6 independent) postsynaptic current frequency. Interestingly, corner preference (measuring the intensity of social defeat) correlated positively with INMDA/IAMPA and eEPSC frequency and negatively with IAMPA/IGABA. Our results suggest that SD induces behaviorally-relevant synaptic rearrangement in mPFC circuits, part of which is IL-6 dependent. In particular, IL-6 is necessary to produce synaptic plasticity leading to stress resilience in some individuals, but to stress sensitivity in others.