Synaptic and extrasynaptic SK2 channels are differentially altered in the hippocampus in Aβ pathology

Calcium signaling mediated by small-conductance calcium-activated potassium (SK) channels plays a critical role in regulating synaptic plasticity and neuronal excitability in the hippocampus. Although SK2 channels are strategically positioned to control calcium-dependent feedback mechanisms, their subcellular organization in Aβ pathology remains poorly understood. Here, we investigated the expression and nanoscale distribution of SK2 channels in the hippocampus of APP/PS1 mice. Using histoblot analysis, we found that overall SK2 protein levels, including the synaptically targeted SK2-L isoform, were not significantly altered in APP/PS1 mice compared with age-matched controls. In contrast, high-resolution SDS-digested freeze-fracture replica labeling revealed a marked and compartment-specific redistribution of SK2 channels. Quantitative analyses demonstrated a significant increase in extrasynaptic SK2 immunoparticles along dendritic membranes, whereas synaptic SK2 localization at postsynaptic densities remained largely preserved. These findings indicate a clear dissociation between SK2 expression and subcellular organization in Aβ pathology. Rather than altering total protein levels, AD selectively remodels the spatial distribution of SK2 channels, preferentially affecting dynamic extrasynaptic pools. This redistribution may have important consequences for the regulation of intrinsic membrane excitability and synaptic integration in hippocampal circuits. More broadly, our results support the concept that disruption of membrane protein organization at the nanoscale level represents a key mechanism underlying early neuronal dysfunction in Aβ pathology.