Prion diseases are neurodegenerative disorders that are characterized by the presence of the misfolded prion protein (PrP). Neurotoxicity in these diseases may result from prion-induced modulation of ion channel function, changes in neuronal excitability, and consequent disruption of cellular homeostasis. We therefore examined PrP effects on a suite of potassium (K 1 ) conductances that govern excitability of basal forebrain neurons. Our study examined the effects of a PrP fragment , 50 nM] on rat neurons using the patch clamp technique. In this paradigm, PrP(106-126) peptide, but not the ''scrambled'' sequence of PrP(106-126), evoked a reduction of whole-cell outward currents in a voltage range between -30 and 130 mV. Reduction of wholecell outward currents was significantly attenuated in Ca 21 -free external media and also in the presence of iberiotoxin, a blocker of calcium-activated potassium conductance. PrP(106-126) application also evoked a depression of the delayed rectifier (I K ) and transient outward (I A ) potassium currents. By using single cell RT-PCR, we identified the presence of two neuronal chemical phenotypes, GABAergic and cholinergic, in cells from which we recorded. Furthermore, cholinergic and GABAergic neurons were shown to express K v 4.2 channels. Our data establish that the central region of PrP, defined by the PrP(106-126) peptide used at nanomolar concentrations, induces a reduction of specific K 1 channel conductances in basal forebrain neurons. These findings suggest novel links between PrP signalling partners inferred from genetic experiments, K 1 channels, and PrP-mediated neurotoxicity. V V C 2010 Wiley-Liss, Inc.