K_IR channel regulation of electrical conduction along cerebrovascular endothelium: Enhanced modulation during...

Endothelial cell (EC) coupling occurs through gap junctions and underlies cerebral blood flow regulation governed by inward-rectifying K⁺ (K_IR ) channels. This study addressed effects of K_IR channel activity on EC coupling before and during Alzheimer's disease (AD).

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 (V_m ) recordings in ECs at distance ~400 μm. Elevated extracellular potassium ([K⁺ ]_E ; 8-15 mmol/L; reference, 5 mmol/L) activated K_IR channels.

Conducted V_m (∆V_m ) 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 ∆V_m 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 .

Brain endothelial K_IR channel activity modulates bidirectional spread of vasoreactive signals with enhanced regulation of EC coupling during AD pathology.