Astrocyte inositol triphosphate receptor type 2 and cytosolic phospholipase A₂ alpha regulate arteriole responses in mouse neocortical brain slices

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.