Status Epilepticus (SE) is a life-threatening condition characterized by continuous or rapidly repeating seizures. It is associated with seizure-induced dysregulation of neurovascular coupling. Transient receptor potential canonical 3 (TRPC3) channels have been shown to be important in the propagation and severity of seizures during SE, and it is known that vascular TRPC3 channels are involved in the regulation of neurovascular coupling, therefore they may also be involved in SE-induced neurovascular uncoupling. In order to examine the roles that TRPC3 channels expressed specifically in vascular smooth muscle cells (VSMCs) or in vascular endothelial cells (VECs) play in SE-induced dysregulation of neurovascular coupling, we developed cell-specific TRPC3 knock out mouse models for smooth muscle cells (TRPC3smcKO) and endothelial cells (TRPC3ecKO).
We show that TRPC3smcKO mice exhibit a greater increase in cerebral blood flow (CBF), a reduction in CBF variability, and a positive correlation between CBF and neural activity during SE. These findings are associated with both a shorter duration of SE and a reduction of seizure-induced neuronal cell death. Surprisingly, TRPC3ecKO mice also exhibit similar maintenance of neurovascular coupling to that of the TRPC3smcKO mice. This is highly unexpected as VEC-expressed TRPC3 channels are thought to only participate in vasodilation, not vasoconstriction. Even more unexpected was the finding that TRPC3ecKO mice are highly protected against pilocarpine-induced SE as only 1 of 8 mice developed seizures.
Neuropeptide Y (NPY) was investigated as a potential upstream mediator of TRPC3. Cortical NPY concentration was found to approximately double during SE. CBF during SE was significantly improved in mice treated with antagonists to either NPY1 receptor or NPY2 receptor. The correlation between CBF and neural activity was significantly increased in mice treated with NPY2 receptor antagonist, suggesting NPY is likely the upstream signaling molecule leading to TRPC3-mediated neurovascular dysfunction.
Our data show that vascular TRPC3 channels mediate SE-induced dysregulation of neurovascular coupling and suggest that this is a critical factor for the progression of SE. Targeting neurovascular uncoupling may provide a novel therapeutic strategy to reduce the sequelae of SE and potentially other neurological disorders.
|Commitee:||Childs, Gwen, Phelan, Kevin, Rhee, Sung, Rusch, Nancy|
|School:||University of Arkansas for Medical Sciences|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 81/2(E), Dissertation Abstracts International|
|Keywords:||Neurovascular coupling, Status Epilepticus, TRPC3|
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