Amyloid-β Protein Precursor Regulates Electrophysiological Properties in the Hippocampus via Altered Kv1.4 Expression and Function in Mice.

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Amyloid-β protein precursor (AβPP) is enriched in neurons. However, the mechanism underlying AβPP regulation of neuronal activity is poorly understood. Potassium channels are critically involved in neuronal excitability. In hippocampus, A-type potassium channels are highly expressed and involved in determining neuronal spiking. We explored hippocampal local field potential (LFP) and spiking in the presence and absence of AβPP, and the potential involvement of an A-type potassium channel. We used in vivo extracellular recording and whole-cell patch-clamp recording to determine neuronal activity, current density of A-type potassium currents, and western blot to detect changes in related protein levels. Abnormal LFP was observed in AβPP-/- mice, including reduced beta and gamma power, and increased epsilon and ripple power. The firing rate of glutamatergic neurons reduced significantly, in line with an increased action potential rheobase. Given that A-type potassium channels regulate neuronal firing, we measured the protein levels and function of two major A-type potassium channels and found that the post-transcriptional level of Kv1.4, but not Kv4.2, was significantly increased in the AβPP-/- mice. This resulted in a marked increase in the peak time of A-type transient outward potassium currents in both glutamatergic and gamma-aminobutyric acid-ergic (GABAergic) neurons. Furthermore, a mechanistic experiment using human embryonic kidney 293 (HEK293) cells revealed that the AβPP deficiency-induced increase in Kv1.4 may not involve protein-protein interaction between AβPP and Kv1.4. This study suggests that AβPP modulates neuronal firing and oscillatory activity in the hippocampus, and Kv1.4 may be involved in mediating the modulation.