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Elevation of energy metabolism and disturbance of astrocyte number/function in the ventral anterior cingulate cortex (vACC) contributes to the pathophysiology of major depressive disorder (MDD). Functional hyperactivity of vACC may result from reduced astrocytic glutamate uptake and increased neuronal excitation. Here we tested this hypothesis by knocking-down astrocytic glutamate transporter GLAST/GLT-1 expression in mouse infralimbic (IL, rodent equivalent of vACC) or prelimbic (PrL) cortices using RNAi strategies. Unilateral siRNA (small interfering RNA) microinfusion targeting GLAST or GLT-1 in mouse IL induced a moderate (20-30%) and long-lasting (7 days) decrease in their expression. Intra-IL GLAST-/GLT-1 siRNA microinfusion reduced the number of glial fibrillary acidic protein (GFAP)-positive and glutamine synthetase (GS)-positive astrocytes and evoked a depressive-like phenotype reversed by citalopram and ketamine. Intra-IL GLAST or GLT-1 knockdown markedly reduced serotonin (5-HT) release in the dorsal raphe nucleus (DR) and induced an overall reduction of brain-derived neurotrophic factor (BDNF) expression in ipsilateral and contralateral hemispheres. Egr-1 (early growth response protein-1) labeling suggests that both siRNAs enhance the GABAergic tone onto DR 5-HT neurons, leading to an overall decrease of 5-HT function, likely related to the widespread reduction on BDNF expression. Conversely, similar reductions of GLAST and GLT-1 expression in PrL did not induce a depressive-like phenotype. These results suggest that a focal glial change in IL translates into global change of brain activity by virtue of the descending projections from IL to DR and the subsequent attenuation of serotonergic function in forebrain, an effect perhaps related to the varied symptomatology of MDD.