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Under control conditions, the peak IBa at �C20 mV was �C2.77 �� 0.26 nA, whereas, in the presence of PrP(106�C126), it was �C2.56 �� 0.22 nA (n = 9; P > 0.05). PrP(106�C126) application resulted in an increase in excitability (Fig. 8A) of unphenotyped DBB neurons, whereas scrambled PrP at the same concentration had no effect. There was a significant increase in neuronal discharge in the presence of PrP(106�C126) compared with control (control = 2.5 �� 0.55 Hz, PrP(106�C126) = 29.5 �� 2.39 Hz, n = 6; *P Pexidartinib datasheet are subject to modulation by ligand- and voltage-dependent channels (Easaw et al., 1997; Jhamandas et al., 2003). In this study, we investigated the effects of a human synthetic peptide [PrP(106�C126)] on the DBB neurons in the basal forebrain. Using nanomolar concentrations of PrP(106�C126), which are among the lowest reported in the literature, we were able to show a significant reduction in a suite of potassium currents, including calcium-activated potassium (IC), the delayed rectifier (IK), and transient outward potassium (IA). However, there was no effect on calcium (barium) or sodium currents. Also, using single-cell RT-PCR analysis, selleck products we demonstrate that PrP(106�C126) had an effect on both GABAergic and cholinergic populations of basal forebrain neurons. Furthermore, the majority of cholinergic and GABAergic neurons also coexpressed Kv4.2, a channel associated with IA currents. The effect of PrP(106�C126) to decrease IC currents without an influence on calcium currents indicates a direct effect on IC channels, rather than an upstream effect on calcium entry into cells (Figs. 5, 6). PrP(106�C126) effects on whole-cell currents are partially blocked in the presence of iberiotoxin, a specific blocker of IC, further supporting the involvement of calcium-activated potassium channels and not calcium channels. IC currents have been shown to be responsible for the repolarization phase of the action potential and hence play a role in the process GUCY1B3 of spike frequency adaptation (��accommodation��; Vergara et al., 1998). The effect of PrP(106�C126) on depressing outward currents through IC channels could result in an increased excitation of DBB neurons, a finding that is supported by our observations during current-clamp recordings. Application of PrP(106�C126) indeed increased the neuronal excitability, as demonstrated in Figure 8A,B. Functionally, IK channels augment action potential repolarization, so PrP(106�C126)-mediated reduction of IK currents would also be expected to result in an increase in the action potential width, and this may play a role in the regulation of cell excitability. Hence the overall effect of PrP(106�C126) on these K+ conductances is anticipated to result in a net excitation of the DBB neurons.