Elucidating the Involvement of Endothelial TRPC3 Channels in Neurovascular Coupling During Status Epilepticus
Authors: Cozart Michael , Rhee Sung , Rusch Nancy , Phelan Kevin , Zheng Fang 
Published: June 2021

Neurovascular coupling is the relationship between local neural activity and resulting changes to blood flow. In a non‐pathological state, local increases in neural activity result in greater metabolic needs which are then satisfied by increased blood flow to the region. As neural activity increases greatly during Status Epilepticus (SE), a commensurate increase in blood flow is also expected. However, we have observed an inverse hemodynamic response at the onset of seizure activity which evidences SE‐induced dysregulation of normal neurovascular coupling. Canonical transient receptor potential channel 3 (TRPC3) is a cation channel that regulates intracellular calcium. Our previous results confirmed its contribution to both physical manifestations of seizure and neural seizure activity in a pilocarpine model of SE. Current literature suggests that TRPC3 channels expressed specifically in cerebrovascular endothelial cells are involved in the regulation of neurovascular coupling and contribute to vasodilation, therefore they may also be involved in its dysregulation during epileptogenesis. In this study, we investigate the precise role of endothelial cell TRPC3 channels in neurovascular coupling during SE.

Endothelial cell‐specific TRPC3 knockout (TRPC3ecKO) mice were generated in house in order to examine the contribution of endothelial TRPC3 channels to the dysregulation of neurovascular coupling during SE. Pilocarpine followed 30 minutes later by PTZ was used to induce Status Epilepticus in urethane‐anesthetized mice. Laser speckle contrast imaging was used simultaneously with electroencephalography (EEG) on TRPC3ecKO mice and littermate controls in order to couple real‐time imaging of cortical blood flow with EEG recording of brain activity during SE.

Moments after administration of pilocarpine, cerebral blood flow is increased in both TRPC3ecKO and littermate controls. The blood flow increase in TRPC3ecKO is significantly greater than controls (185% of baseline vs 144%, respectively). Immediately following PTZ injection, cortical blood flow in TRPC3ecKO exhibited a fast return to baseline which was then followed by a slow, steady increase which correlated positively with EEG activity preceding the onset of SE, whereas cortical blood flow in control mice remained unchanged prior to the onset of SE and thus showed no correlation. At the onset of SE, there is a large increase in EEG activity. In control mice, this is coupled with an inverse hemodynamic response observed as a sharp reduction in cortical blood flow. In TRPC3ecKO mice, this inverse hemodynamic response is completely absent as cortical blood flow continues the steady increase observed prior to the onset of SE, and is again positively correlated with EEG activity.

These findings demonstrate that during SE, there is dysregulation of neurovascular coupling observed as a paradoxical inverse hemodynamic response. We suggest that endothelial TRPC3 channels contribute to vasoconstriction underlying SE‐induced neurovascular coupling dysfunction.

Support or Funding Information

UAMS Hornick Endowment for Research into Stroke & Related Disorders, Fund to Cure Stroke Foundation

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.