ABSTRACTIntroductionThe receptor SorCS2 is involved in the trafficking of membrane receptors and transporters. It has been implicated in brain disorders and has previously been reported to be indispensable for ionotropic glutamatergic neurotransmission in the hippocampus.AimWe aimed to study the role of SorCS2 in the control of astrocyte‐neuron communication, critical for neurovascular coupling.MethodsBrain slices from P8 and 2‐month‐old wild‐type and SorCS2 knockout (Sorcs2−/−) mice were immunostained for SorCS2, GFAP, AQP4, IB4, and CD31. Neurovascular coupling was assessed in vivo using laser speckle contrast imaging and ex vivo in live brain slices loaded with calcium‐sensitive dye. Bulk and cell surface fraction proteomics was analyzed on freshly isolated and cultured astrocytes, respectively, and validated with Western blot and qPCR.ResultsSorCS2 was strongly expressed in astrocytes, primarily in their endfeet, of P8 mice; however, it was sparsely represented in 2‐month‐old mice. Sorcs2−/− mice demonstrated reduced neurovascular coupling associated with a reduced astrocytic calcium response to neuronal excitation. No differences in vascularization or endothelium‐dependent relaxation ex vivo between the 2‐month‐old groups were observed. Proteomics suggested changes in glutamatergic signaling and suppressed calcium signaling in Sorcs2−/− brains from both P8 and 2‐month‐old mice. The increased abundance of glutamate metabotropic receptor 3 in Sorcs2−/− astrocytes was validated by PCR and Western blot. In cultured Sorcs2−/− astrocytes, AQP4 abundance was increased in the bulk lysate but reduced in the cell surface fraction, suggesting impaired trafficking.ConclusionThe results suggest that SorCS2 expression is important for the development of neurovascular coupling, at least in part by modulating glutamatergic and calcium signaling in astrocytes.