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

Abstract

Endothelial cell (EC) coupling occurs through gap junctions and underlies cerebral blood flow regulation governed by inward-rectifying (KIR ) channels. This study addressed effects of KIR 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 (Vm ) recordings in ECs at distance ~400 μm. Elevated extracellular potassium ([K+ ]E ; 8-15 mmol L-1 ; reference, 5 mmol L-1 ) activated KIR channels. Conducted Vm (∆Vm ) responses ranged from ~-30 to 30 mV in response to -3 to +3 nA (linear regression, R2 ≥0.99) while lacking rectification for charge polarity or axial direction of spread. Conduction slope decreased ~10-20% during 15 mmol L-1 [K+ ]E in Pre-AD males and AD females. 15 mmol L-1 [K+ ]E decreased conduction at lower thresholds in AD animals (~±20 mV) versus Pre-AD (~±25 mV). AD increased (~10-15%) conducted hyperpolarization during 8-12 mmol L-1 [K+ ]E . Brain endothelial KIR channel activity modulates bidirectional spread of vasoreactive signals with enhanced regulation of EC coupling during AD pathology.