Synaptic-like transmission between neural axons and arterial smooth muscle cells drives cerebral neurovascular coupling

Normally functioning brains depend on neurovascular coupling (NVC) and its dysfunction underlies many neuropathologies. Although cell-type specificity has been implicated in NVC, how active neural information is specifically conveyed to the targeted arterioles in the brain remains poorly understood. Here, using two-photon focal optogenetics in the mouse cerebral cortex, we demonstrated that single glutamatergic axons dilate their innervating arterioles via synaptic-like transmission between neural-arteriolar smooth muscle cells junction (NsMJ). The presynaptic parental-daughter bouton makes dual innervations on postsynaptic dendrites and on arteriolar smooth muscles cells (aSMCs), which expressed many types of neuromediator receptors, including glutamate NMDA receptor subunit 1 (Grin1). Disruption of NsMJ transmission, by aSMC specific knockout of GluN1, diminished the optogenetic and whisker stimulation-caused functional hyperemia. Notably, the absence of GluN1 subunit in aSMCs protected the brain atrophy from cerebral ischemia by preventing Ca2+ overload in aSMCs during arteriolar constriction caused by the ischemia-induced spreading depolarization. Our findings reveal that NsMJ transmission drives neurovascular coupling and also open up a new avenue for studying stroke. mRNA profiles of arteriolar smooth muscle cell, cortical cell and astrocyte