A pericyte Cl- clamp controls capillary electrical signaling and brain blood flow

Neurons lack substantial energy stores and thus their function is critically dependent on the timely delivery of energy substrates in the blood. Precise control of brain blood flow is therefore essential for brain health. However, the exact mechanisms through which cerebral hemodynamics are regulated remain unclear. Furthering our

understanding of this control is critical, as it is increasingly appreciated that disruption of brain blood flow is one of the earliest pathological events in Alzheimer’s disease and related disorders and may be a key contributory factor to disease progression and neurodegeneration. Thus, advancing our understanding of the mechanisms of

brain blood flow control may reveal novel and much needed targets for therapeutic interventions. Thin-strand pericytes are mural cells that reside on brain capillaries deep within the vascular network, interposed between capillary endothelial cells and astrocytic endfeet. It is thought that thin-strand pericytes contribute to the

control of brain blood flow but a detailed mechanistic understanding of this process is lacking. Based on the compelling preliminary data in this proposal, we suggest a novel dimension to thin-strand pericyte control of electrical signaling throughout the vascular network—from capillaries to arterioles—which plays a central role in

blood flow control. Specifically, we identify for the first time a “pericyte chloride clamp” mechanism that counterbalances hyperpolarizing electrical signaling to precisely control local blood flow. The activity of thin- strand pericyte calcium-activated chloride channels is central to this mechanism, and these are controlled by

calcium signals generated by membrane voltage-dependent calcium channels and endoplasmic reticulum calcium release channels. This signaling module is tethered to neuronal activity through the activity of thin-strand pericyte metabotropic glutamate receptors, activation of which shuts off the pericyte chloride clamp to augment

hyperpolarizing electrical signaling and increase blood flow to the active network. Using these exciting findings as a springboard, we propose to define the precise mechanisms through which calcium-activated chloride channels are controlled in thin-strand pericytes, how these channels contribute to the

control of capillary blood flow by shaping electrical signals, and how neuronal activity toggles the pericyte chloride clamp on and off to regulate local blood flow on a moment-to-moment basis to satisfy fluctuating neuronal energy needs. Completion of this work may thus identify novel therapeutic targets in thin-strand pericytes and could lay

the groundwork for much needed treatments aimed at protecting or rescuing blood flow in brain disorders with a vascular component.