Major depression (MD) is a common and disabling disorder but knowledge of its pathophysiology is still incomplete. In the last years, degenerations or dysfunctions of glial cells, especially astrocytes, have been postulated to play a critical role in the pathogenesis of depression. Glial loss in prefrontal and limbic brain regions was observed in depressed patients and in animal models of stress and depression. Degeneration of astrocytes resulted in an excess glutamate in the synaptic cleft and glutamate/GABA imbalance in the affected structures. This review presents an up-to-date information concerning the role of glial cells in maintenance of glutamate/GABA balance in the brain tripartite glutamatergic synapses; discusses the importance of glial pathology and presents models of depression based on astrocyte impairment. The model of degeneration of astrocytes in the medial prefrontal cortex of the rat, induced by the specific astrocytic toxin α-aminoadipic acid, is presented as a valuable model for studying antidepressant compounds.