Abstract: Objective To study the behavioral changes of inositol 1,4,5-trisphosphate receptor type 2 knockout (Itpr2 -/- mice) and investigate the blood perfusion changes in the hippocampus using three-dimensional arterial spin labeling (3D-ASL). Methods 28 Itpr2 -/- mice and 20 wild-type mice were assessed for depressive phenotype using behavioral tests (including sucrose consumption test, tail suspension test, forced swimming test and open field test). 15 Itpr2 -/- mice and 14 wild- type mice were randomly selected for 3D-T2WI imaging of the whole brain and 3D-ASL imaging of the middle hippocampal layer, and cerebral blood flow (CBF) of the middle hippocampal layer was calculated. ITK-SNAP was used to delineate the bilateral hippocampal area and measure the average CBF value. Results Compared with the wild- type mice, Itpr2 -/- mice exhibited a distinct depressive phenotype with significantly decreased sucrose preference (P<0.05) and increased immobile time in tail suspension test (P<0.05) and forced swimming test (P<0.01), without obvious changes in the performance in open field test (P> 0.05). Significantly decreased mean CBF values were found in the left and right hippocampus of Itpr2 -/- mice as compared with the wild-type mice (left: 73.30 ±5.609 vs 95.77±5.095; right: 73.53±5.700 vs 100.5±4.696; bilateral means: 73.42±5.607 vs98.12±4.754; P<0.01). Conclusion Itpr2 deficiency can cause depressive phenotype and affect the cerebral blood flow in the hippocampus of mice.