Astrocyte Inositol Triphosphate Receptor Type 2 and Cytosolic Phospholipase A2 Alpha Regulate Arteriole Responses in Mouse Neocortical Brain Slices

Abstract

Functional hyperemia of the cerebral vascular system matches regional blood flow to the metabolic demands of the brain. One current model of neurovascular control holds that glutamate released by neurons activates group I metabotropic glutamate receptors (mGluRs) on astrocytes, resulting in the production of diffusible messengers that act to regulate smooth muscle cells surrounding cerebral arterioles. The acute mouse brain slice is an experimental system in which changes in arteriole diameter can precisely measured with light microscopy. Stimulation of the brain slice triggers specific cellular responses that can be correlated to changes in arteriole diameter. Here we used inositol trisphosphate receptor type 2 (IP3R2) and cytosolic phospholipase A2 alpha (cPLA2α) deficient mice to determine if astrocyte mGluR activation coupled to IP3R2-mediated Ca2+ release and subsequent cPLA2α activation is required for arteriole regulation. We measured changes in astrocyte cytosolic free Ca2+ and arteriole diameters in response to mGluR agonist or electrical field stimulation in acute neocortical mouse brain slices maintained in 95% or 20% O2. Astrocyte Ca2+ and arteriole responses to mGluR activation were absent in IP3R2− /− slices. Astrocyte Ca2+ responses to mGluR activation were unchanged by deletion of cPLA2α but arteriole responses to either mGluR agonist or electrical stimulation were ablated. The valence of changes in arteriole diameter (dilation/constriction) was dependent upon both stimulus and O2 concentration. Neuron-derived NO and activation of the group I mGluRs are required for responses to electrical stimulation. These findings indicate that an mGluR/IP3R2/cPLA2α signaling cascade in astrocytes is required to transduce neuronal glutamate release into arteriole responses.