Accumulation of amyloid β (Aβ) peptides constitutes the neuropathological hallmark of Alzheimer’s disease(AD). According to the amyloid hypothesis, the accumulation of Aβ results in progressive loss of synaptic efficacy. K⁺ channels regulate a number of processes: the resting potential, keeping action potentials short, timing interspike intervals and synaptic plasticity¹. A number of studies have shown that Aβ alters properties of K⁺ currents in neurons^2,3,4. We have previously reported a possible physiological role for the soluble Aβ_1-40 peptide in modulating ‘A’-type K⁺ channels in cerebellar granule neurons^3,4. In this study we use organotypic hippocampal slices to mimic the in vivo modulation of K⁺ channels by soluble rat recombinant Aβ_1-40 over 24 hours. Whole-cell patch clamp measurements of K⁺ channel currents were carried out using organotypic hippocampal slices prepared from 8-10 day old rats using the Stoppini method⁵. The extracellular solution contained aCSF consisting of (mM): 126 NaCl,3KCl,1.25NaH₂PO₄,2MgSO₄, 2CaCl₂.2H₂0,10 glucose and 24 NaHCO₃. Intracellular solution contained (mM): 140KCl, 0.5CaCl₂, 5EGTA, 10HEPES and 2K-ATP. Rat recombinant Aβ_1-40 was solubilised in DMSO before dilution in culture media to a concentration of 10nM and applied to slices for 24 hours. The reverse Aβ_40-1 peptide was used as control. Statistical differences were assessed using repeated measures ANOVA with Tukey’s post-hoc test or an unpaired Student’s t-test. Rat recombinant Aβ_1-40 caused a significant 3.5 fold increase in the peak K⁺ channel current density/voltage (I-V) relationship in slices (n=6 controls, n=7 Aβ-treated cells). At a test potential of +50mV, current increased from 20.0±0.01 pA/pF in the control to 90.0±0.02pA/pF. Peak K⁺ channel current was further separated by their inactivation properties into fast inactivating ‘A’-type(I_KA) and non-inactivating delayed rectifier (I_KV) components. In order to isolate the two components, cells were prepulsed to a potential of -140mV and measurements of the peak current was subtracted from the current at the end of the test step (peak-end). The I_KA component of the K⁺ current I-V was particularly sensitive to the effects of rat recombinant Aβ_1-40, with a significant 5 fold increase in K⁺ channel current density when compared to the control. At a test potential of +50mV, current increased from 5.0±0.01 pA/pF in the control to 30.0±0.01 pA/pF in Aβ-treated cells. There was no significant difference in I_KV. The data from this study corroborate our previous findings, supporting a physiological role for the Aβ_1-40 peptide as a modulator of K⁺ channels, in particular the I_KA component. I_KA channels have been implicated in the onset of LTP in neurons, which is thought to underlie learning and memory¹. A disruption in this physiological modulation may therefore result in a disruption of synaptic plasticity, classic to AD.