This R01 application focuses on the underlying mechanisms of neurovascular coupling dysfunction. The brain
consumes a large amount of energy which must be supplied as oxygen and glucose by blood flow. Neurovascular
coupling, a mechanism that matches local neuronal activity to blood flow, is critical to maintain local
microenvironment and normal brain function. However, normal neurovascular coupling is disrupted in seizure,
traumatic brain injury, and other neurological disorders. Despite continued high neuronal metabolism, small
cerebral arteries and arterioles begin to inappropriately constrict to limit CBF to the challenged neurons. This
pathogenic vasoconstriction, termed the “inverse hemodynamic response” (IHR), is thought to contribute to
brain damage and functional impairment in these neurological diseases. The mechanism of IHR is unknown.
This proposal seeks to test a novel hypothesis that seizure-induced IHR is mediated by an endothelial signaling
pathway consisted of Neuropeptide Y Receptor 1 (NPYR1), Transient Receptor Potential (Canonical) 3 (TRPC3)
channels, and endothelin 1 (ET1). We generated inducible and brain-specific endothelial TRPC3 knockout line
and NPYR1 knockout line. These novel mouse lines will be used in combination with NPYR1, TRPC3 and ET1
receptor selective inhibitors to test our hypothesis. Aim 1 will demonstrate the existence of an endothelial
NPYR1-TRPC3-ET1 signaling pathway that mediates cerebral vasoconstriction using acutely isolated brain
parenchymal arterioles and cranial window preparations in vivo. Aim 2 will show that the same signaling
pathway mediates seizure-induced IHR. Aim 3 will determine whether disruption of this signaling pathway will
reduce susceptibility to seizures and their deleterious consequences. The studies rely on complementary areas
of expertise pooled by a research team with expertise in cerebrovascular reactivity, epilepsy and
neuroinflammation and neurodegeneration. Collectively, these experiments will reveal new mechanistic
insights regarding IHR and may lead to new treatments for epilepsy and other neurological diseases.
