Pericyte pannexin1 controls hippocampal capillary diameter and recognition memory

Abstract In the brain-blood-barrier, contractile pericytes fine-tune the capillary resistance and blood supply to meet neuro-metabolic demands; molecular players governing these functions remain undefined. The protein subunit pannexin1 (Panx1), assembles into transmembrane large-pore hemichannels (Panx1HCs) mediating the release of ATP, a regulator of pericyte contractility and capillary resistance. Until now, the expression and role of pericyte Panx1 in brain physiology were unknown. Here, we report that cerebral pericytes express functional Panx1HCs. Pericyte-specific Panx1 is required for recognition memory and hippocampal capillary dilation induced by pharmacological activation of glutamatergic synaptic transmission, which underlies functional hyperaemia. Mechanistically, pericyte Panx1 is modulated by glutamatergic NMDA/AMPA and purinergic P2X7/P2Y6 receptors and controls ATP release influencing pericyte Ca2+ and hippocampal capillary diameter dynamics. Our study unveils pericyte Panx1 as a novel physiological regulator of cerebral capillary resistance, crucial for sustaining higher brain functions and a potential therapeutic target for cognitive disorders associated with cerebrovascular diseases.