Increased K(V)2.1 Channel Clustering Underlies the Reduction of Delayed Rectifier K(+) Currents in Hippocampal Neurons of the Tg2576 Alzheimer’s Disease Mouse

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the progressive deterioration of cognitive functions. Cortical and hippocampal hyperexcitability intervenes in the pathological derangement of brain activity leading to cognitive decline. As key regulators of neuronal excitability, the voltage-gated K(+) channels (K(V)) might play a crucial role in the AD pathophysiology. Among them, the K(V)2.1 channel, the main α subunit mediating the delayed rectifier K(+) currents (I(DR)) and controlling the intrinsic excitability of pyramidal neurons, has been poorly examined in AD. In the present study, we investigated the K(V)2.1 protein expression and activity in hippocampal neurons from the Tg2576 mouse, a widely used transgenic model of AD. To this aim we performed whole-cell patch-clamp recordings, Western blotting, and immunofluorescence analyses. Our Western blotting results reveal that K(V)2.1 was overexpressed in the hippocampus of 3-month-old Tg2576 mice and in primary hippocampal neurons from Tg2576 mouse embryos compared with the WT counterparts. Electrophysiological experiments unveiled that the whole I(DR) were reduced in the Tg2576 primary neurons compared with the WT neurons, and that this reduction was due to the loss of the K(V)2.1 current component. Moreover, we found that the reduction of the K(V)2.1-mediated currents was due to increased channel clustering, and that glutamate, a stimulus inducing K(V)2.1 declustering, was able to restore the I(DR) to levels comparable to those of the WT neurons. These findings add new information about the dysregulation of ionic homeostasis in the Tg2576 AD mouse model and identify K(V)2.1 as a possible player in the AD-related alterations of neuronal excitability.