LAUSR

Brain energetics disturbance is a hypothesized cause of depression. Glucose is the predominant fuel of brain energy metabolism, however, the cell-specific change of glucose metabolism and underlying molecular mechanism in depression remain unclear. In this study, we firstly applied 18 F-FDG PET and observed brain glucose hypometabolism in prefrontal cortex (PFC) of corticosterone-induced depression of rats. Next, astrocytic glucose hypometabolism was identified in PFC slices in in both corticosterone-induced depression of rats and cultured primary astrocytes from newborn rat PFC after stress-level corticosterone (100 nM) stimulation. Furthermore, we found the blockage of glucose uptake and the decrease of plasma membrane (PM) translocation of glucose transporter 1 (GLUT1) in astrocytic glucose hypometabolism under depressive condition. Interestingly, thioredoxin interacting protein (TXNIP), a glucose metabolism sensor and controller, was found to be overexpressed in corticosterone-stimulated astrocytes in vivo and in vitro. High TXNIP level could restrict GLUT1-mediated glucose uptake in primary astrocytes in vitro. Adeno-associated virus vector-mediated astrocytic TXNIP overexpression in rat medial PFC suppressed GLUT1 PM translocation, consequently developed depressive-like behavior. Conversely, TXNIP siRNA facilitated GLUT1 PM translocation to recover glucose hypometabolism in corticosterone-exposed cultured astrocytes. Notably, astrocyte-specific knockdown of TXNIP in medial PFC of rats facilitated astrocytic GLUT1 PM translocation, showing obvious antidepressant activity. These findings provide a new astrocytic energetic perspective in the pathogenesis of depression, more importantly, provide TXNIP as a promising molecular target for novel depression therapy.