KIR channel regulation of electrical conduction along cerebrovascular endothelium: Enhanced modulation during Alzheimer's disease

Abstract

Objective: Endothelial cell (EC) coupling occurs through gap junctions and underlies cerebral blood flow regulation governed by inward-rectifying K+ (KIR) channels. This study addressed effects of KIR channel activity on EC coupling before and during Alzheimer's disease (AD). Methods: Intact EC tubes (width: ~90–100 μm; length: ~0.5 mm) were freshly isolated from posterior cerebral arteries of young Pre-AD (1–3 months) and aged AD (13–18 months) male and female 3xTg-AD mice. Dual intracellular microelectrodes applied simultaneous current injections (±0.5–3 nA) and membrane potential (Vm) recordings in ECs at distance ~400 μm. Elevated extracellular potassium ([K+]E; 8–15 mmol/L; reference, 5 mmol/L) activated KIR channels. Results: Conducted Vm (∆Vm) responses ranged from ~−30 to 30 mV in response to −3 to +3 nA (linear regression, R2 ≥.99) while lacking rectification for charge polarity or axial direction of spread. Conduction slope decreased ~10%–20% during 15 mmol/L [K+]E in Pre-AD males and AD females. 15 mmol/L [K+]E decreased conduction by ~10%–20% at lower ∆Vm thresholds in AD animals (~±20 mV) versus Pre-AD (~±25 mV). AD increased conducted hyperpolarization by ~10%–15% during 8–12 mmol/L [K+]E. Conclusions: Brain endothelial KIR channel activity modulates bidirectional spread of vasoreactive signals with enhanced regulation of EC coupling during AD pathology.