In addition to mediating conventional quantal synaptic transmission (also known as phasic inhibition), gamma-aminobutyric acidA (GABAA) receptors have been recently shown to underlie a slower, persistent form of inhibition (tonic inhibition). Using patch-clamp electrophysiology and immunohistochemistry, we addressed here whether a GABAA receptor-mediated tonic inhibition is present in supraoptic nucleus (SON) neurosecretory neurons; identified key modulatory mechanisms, including the role of glia; and determined its functional role in controlling SON neuronal excitability. Besides blocking GABAA-mediated inhibitory postsynaptic currents, the GABAA receptor blockers bicuculline and picrotoxin caused an outward shift in the holding current (I(tonic)), both in oxytocin and vasopressin neurons. Conversely, the high-affinity antagonist gabazine selectively blocked inhibitory postsynaptic currents. Under basal conditions, I(tonic) was independent on the degree of synaptic activity but was strongly modulated by the activity GABA transporters (GATs), mostly the GAT3 isoform, found here to be localized in SON glial cells/processes. Extracellular activation of GABAergic afferents evoked a small gabazine-insensitive, bicuculline-sensitive current, which was enhanced by GAT blockade. These results suggest that I(tonic) may be activated by spillover of GABA during conditions of strong and/or synchronous synaptic activity. Blockade of I(tonic) increased input resistance, induced membrane depolarization and firing activity, and enhanced the input-output function of SON neurons. In summary, our results indicate that GABAA receptors, possibly of different molecular configuration and subcellular distribution, mediate synaptic and tonic inhibition in SON neurons. The latter inhibitory modality plays a major role in modulating SON neuronal excitability, and its efficacy is modulated by the activity of glial GATs.

The inhibitory neurotransmitter GABA plays a key role in the modulation of paraventricular nucleus (PVN) neuronal excitability and sympathoexcitatory outflow, under both physiological and pathological conditions. In addition to mediating conventional synaptic transmission (phasic inhibition), GABA A receptors of distinct biophysical, molecular and pharmacological properties have been recently found to underlie a slower, persistent form of inhibition (tonic inhibition). Whether the 'tonic' inhibitory modality is present in presympathetic PVN neurons, and what its role is in modulating their activity is at present unknown. Here, we combined tract-tracing techniques with patch-clamp electrophysiology to address these questions. Recordings obtained from PVN-RVLM (rostral ventrolateral medulla) projecting neurons show that besides blocking GABA A -mediated inhibitory postsynaptic currents (IPSCs, I phasic ), the GABA A receptor blockers bicuculline and picrotoxin caused an outward shift in the holding current (I tonic ). Conversely, the high affinity GABA A blocker gabazine blocked I phasic without affecting I tonic . THIP, a GABA A receptor agonist that preferentially activates δ-over γ-containing receptors, enhanced the magnitude of I tonic . Our results also indicate that during conditions of strong and/or synchronous synaptic activity, I tonic may be activated by spillover of synaptically released GABA. Blockade of I tonic induced membrane depolarization, increased firing activity, and enhanced the input-output function of PVN-RVLM neurons. Altogether, our results support the presence of a persistent GABA A -mediated inhibitory modality in presympathetic PVN neurons, which plays a major role in modulating their excitability and firing activity.

Hyperglycaemia-induced oxidative stress makes an important contribution to the aetiology of diabetic neuropathy. The aim of our study was to evaluate the effect of the antioxidant stobadine (STB) in comparison with a treatment by a high-dose of α-lipoic acid (ALA), on the neurological consequences of chronic hyperglycaemia in an animal model of diabetes in Wistar rats (16 weeks old), made diabetic by streptozotocin (STZ 3 × 20 mg i.v.). Neuropathy was evaluated electrophysiologically by measuring motor nerve conduction velocity (NCV) in the 4 th and 8 th week in vivo and motor NCV and resistance to ischaemic conduction failure (RICF) of the sciatic nerve in the 10 th week of the experiment in vitro. The therapy with ALA (100 mg/kg i.p., 5 times a week) and STB (25 mg/kg i.p., 5 times a week) had a significant effect on NCV in vivo in the 8 th week of the experiment and no effect in the 10 th week in vitro. The RICF elevated in diabetic animals was significantly modified by ALA. The effect of the antioxidant STB on NCV was comparable with that of ALA, while RICF was affected only by ALA. We conclude that treatment with appropriate antioxidants might partially prevent nerve dysfunction in diabetic rats.

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Backround: We hypothesized that the levels of some markers could be changed in MS in comparison with controls. We studied five inflammatory markers (interleukin-6, interleukin-8, interleukin-10, beta-2-microglobulin, orosomucoid). Methods: The study was based on CSF and serum examination in patients with MS and control group (patients with non-inflammatory disease). In the MS patients, the lumbar puncture was indicated and performed at the time of the first clinical symptoms compatible with MS. None of our patients had been treated by corticosteroids before lumbar puncture. The aim of the study was to assess CSF and serum levels of inflammatory markers and compare these levels between MS group and control group. We tried to find inflammatory changes in early stage of MS. Results: CSF and serum examination was performed in 102 patients with newly diagnosed MS meeting McDonald's revised diagnostic criteria (70 females; median 40 years) and 102 control group patients (79 females; median 37,5 years). No statistically significant differences in demographic data between MS patients and control group were found. Significantly higher CSF levels of IL-8 (median 59,1; p b 0.0001, Mann-Whitney U test) and beta-2-microglobulin (median 1,27; p b 0.0001, Mann-Whitney U test) in MS patients group were found. Significantly lower serum levels of IL-8 (median 8,00, p = 0,018, Mann-Whitney U test) were found. Conclusion:The levels of two studied inflammatory markers were found to be increased at the time of first clinical symptoms of MS. As the etiology of MS is still unknown, research on inflammatory and neurodegenerative markers in MS should continue.