Syncytial coupling of mid-capillary pericytes underlies seizure-associated electro-metabolic signaling

Disturbances of neurovascular coupling (NVC) contribute to metabolic derailment and neurological symptoms associated with epilepsy. While postictal arterial constriction can be alleviated by inhibitors of voltage gated calcium channels (VGCCs), less is known regarding seizure-associated electrical signals in higher-order capillaries and their role in determining pericyte tone during seizures. Here we investigated electrical signaling within the ex vivo neurovascular unit (NVU) derived from rat and human brain tissue. We focused on electrical signal transduction between pericytes and endothelial cells and the potential role of VGCCs in vasomotion. Using dye coupling and paired patch-clamp recordings, we showed that morphologically heterogeneous groups of mid-capillary pericytes build a functional syncytium with endothelial cells. Coupling was asymmetric, allowing for directed propagation of electrical signals. Regardless of their morphology, mid-capillary pericytes responded with depolarization and constriction to metabotropic receptor (GPCR) activation (by thromboxane, norepinephrine and UDP-glucose). However, depolarization via the patch pipette induced neither Ca2+-influx nor constriction, suggesting lack of contribution of VGCCs to vasomotion. On inducing epileptiform activity, A2a adenosine receptors and inwardly rectifying potassium channels hyperpolarized the capillary syncytium, followed by repeated depolarizations due to seizure-associated potassium increase in the parenchyma. Thus, while mid-capillary pericytes are contractile, their tone does not rely on their membrane potential and VGCCs. However, syncytial coupling allows for transmission of seizure-associated hyper- and depolarizing signals to upstream feeding arterioles. Significance statementElectro-metabolic signaling is a mechanism, which couples neuronal metabolic activity to local blood flow, by generation and conduction of hyperpolarizing electrical signals in the vasculature. Repeated seizures are followed by postictal hypoperfusion, suggesting disturbances in this signaling mechanism. Due to the inaccessibility of mid capillary pericytes, little is known about how seizure-associated electrical signals modulate local capillary tone. O_LIRat and human mid-capillary pericytes are contractile and actively regulate capillary diameter upon GPCR activation. C_LIO_LIWhile GPCR-induced vasoconstriction is associated with depolarization of the pericytes, depolarization via the patch pipette induces neither constriction nor intracellular Ca2+ increases. C_LIO_LIDespite differences in their morphology, mesh and thin strand pericytes participate in a common electrical syncytium along with the capillary endothelial cells both in rat and in human tissue. C_LIO_LISignal transmission at electrical synapses between pericyte-pericyte and pericyte-endothelial cell pairs is asymmetric, suggesting a preferred direction of propagation of electrical signals. C_LIO_LIActivation of A2a adenosine receptors and Kir channels mediate capillary hyperpolarization prior to the onset of seizures, which is followed by seizure-associated depolarization due to extracellular potassium accumulation. C_LI