The M-current (I(K(M))) is believed to modulate neuronal excitability by producing spike frequency adaptation (SFA). Inhibitors of M-channels, such as linopirdine and 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone (XE991), enhance depolarization-induced transmitter release and improve learning performance in animal models. As such, they are currently being tested for their therapeutic potential for treating Alzheimer's disease. The activity of these blockers has been associated with the reduction of SFA and the depolarization of the membrane observed when I(K(M)) is inhibited. To test whether this is the case, the perforated patch technique was used to investigate the capacity of I(K(M)) inhibitors to alter the resting membrane potential and to reduce SFA in mouse superior cervical ganglion neurons in culture. Linopirdine and XE991 both proved to be potent blockers of I(K(M)) when the membrane potential was held at -30 mV (IC(50) 2.56 and 0.26 microM, respectively). However, their potency gradually declined upon membrane hyperpolarization and was almost null when the membrane potential was kept at -70 mV, indicating that their blocking activity was voltage dependent. Nevertheless, I(K(M)) could be inhibited at these hyperpolarized voltages by other inhibitors such as oxotremorine-methiodide and barium. Under current-clamp conditions, neither linopirdine (10 microM) nor XE991 (3 microM) was effective in reducing the SFA and both provoked only a small slowly developed depolarization of the membrane (2.27 and 3.0 mV, respectively). In contrast, both barium (1 mM) and oxotremorine-methiodide (10 microM) depolarized mouse superior cervical ganglion neurons by about 10 mV and reduced the SFA. In contrast to classical I(K(M)) inhibitors, the activity of linopirdine and XE991 on the I(K(M)) is voltage dependent and, thus, these newly developed I(K(M)) blockers do not reduce the SFA. These results may shed light on the mode of action of these putative cognition enhancers in vivo.

The basis of rhythmic activity observed at the dorsal column nuclei (DCN) is still open to debate. This study has investigated the electrophysiological properties of isolated DCN neurones deprived of any synaptic influence, using the perforated-patch technique. About half of the DCN neurones (64/130) were spontaneously active. More than half of the spontaneous neurones (36/64) showed a low threshold membrane oscillation (LTO) with a mean frequency of 11.4 Hz (range: 4.3-22.1 Hz, n = 20; I = 0). Cells showing LTOs also invariably showed a rhythmic 1.2 Hz clustering activity (groups of 2-5 action potentials separated by silent LTO periods). Also, more than one-third of the silent neurones presented clustering activity, always accompanied by LTOs, when slightly depolarised. The frequency of LTOs was voltage dependent and could be abolished by TTX (0.5 microM) and riluzole (30 microM), suggesting the participation of a sodium current. LTOs were also abolished by TEA (15 mM), which transformed clustering into tonic activity. In voltage clamp, most DCN neurones (85%) showed a TTX-/riluzole-sensitive persistent sodium current (INa,p), which activated at about -60 mV and had a half-maximum activation at -49.8 mV. An M-like, non-inactivating outward current was present in 95% of DCN neurones, and TEA (15 mM) inhibited this current by 73.7 %. The non-inactivating outward current was also inhibited by barium (1 mM) and linopirdine (10 microM), which suggests its M-like nature; both drugs failed to block the LTOs, but induced a reduction in their frequency by 56 and 20%, respectively. These results demonstrate for the first time that DCN neurones have a complex and intrinsically driven clustering discharge pattern, accompanied by subthreshold membrane oscillations. Subthreshold oscillations rely on the interplay of a persistent sodium current and a non-inactivating TEA-sensitive outward current.

This paper considers sequencing situations with due date criteria. Three di erent t ypes of criteria are considered: the weighted penalty criterion, the weighted tardiness criterion and the completion time criterion. The main focus is on convexity of the associated cooperative games.

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Non-adapting superior cervical ganglion (SCG) neurones with a clustering activity and sub-threshold membrane potential oscillations were occasionally recorded, suggesting the presence of a persistent sodium current (I(NaP)). The perforated-patch technique was used to establish its properties and physiological role. Voltage-clamp experiments demonstrated that all SCG cells have a TTX-sensitive I(NaP) activating at about -60 mV and with half-maximal activation at about -40 mV. The mean maximum I(NaP) amplitude was around -40 pA at -20 mV. Similar results were achieved when voltage steps or voltage ramps were used to construct the current-voltage relationships, and the general I(NaP) properties were comparable in mouse and rat SCG neurons. I(NaP) was inhibited by riluzole and valproate with an IC(50) of 2.7 and 3.8 microM, respectively, while both drugs inhibited the transient sodium current (I (NaT)) with a corresponding IC(50) of 34 and 150 microM. It is worth noting that 30 microM valproate inhibited the I(NaP) by 70% without affecting the I(NaT). In current clamp, valproate (30 microM) hyperpolarised resting SCG membranes by about 2 mV and increased the injected current necessary to evoke an action potential by about 20 pA. Together, these results demonstrate for the first time that a persistent sodium current exists in the membrane of SCG sympathetic neurones which could allow them to oscillate in the sub-threshold range. This current also contributes to the resting membrane potential and increases cellular excitability, so that it is likely to play an important role in neuronal behaviour.