According to the World Health Organization (WHO) 121 million people suffer from Major Depressive Disorder (MDD) and about 30% of these patients fail to respond to the present therapies. This not only makes MDD a commonly-occurring disorder, but with 50% of all suicide victims having MDD, it has become a global health concern(1,2). MDD is a multifactorial disease on multiple levels ((epi)genetic factors, environmental factors, developmental factors and this contributes to low efficacy of current treatment. Depression has a lot of diagnostic criteria/symptoms (3), but anhedonia and cognitive dysfunction are two of the worst. (4) Many different brain areas, cell interactions and biochemical processes have been examined to clarify the aetiology of MDD, leading to many different hypotheses. Despite this, the underlying pathophysiology of Major Depression is still not fully understood.??A major breakthrough was the monoamine hypothesis, which led to both more understanding and also therapeutical treatments. (2) In recent times, the research area is not that fixed on monoamines anymore. Additional molecular mechanisms underlying depressive pathology have come to light, including glutamatergic neurotransmission and abnormalities in the prefrontal cortex (PFC). These PFC abnormalities may be a key regulator of depression-induced anhedonia (4, 5) and the disturbances of the glutamatergic neurotransmission in the central nervous system is suggested to contribute to the pathophysiology of MDD.??In the mammalian Central Nervous System (CNS) glutamate is the major excitatory neurotransmitter. Glutamate receptors and transporters are abundantly present in the pre- and post-synapse of the neurons and in glia cells, especially in astrocytes. (6) While astrocytes were first considered as supportive cells, at present, accumulating evidence supports the notion ofthem playing a central role in the glutamate metabolism in the brain. (7) Together, a neuronal presynaptic terminal, a postsynaptic spine and an astrocytic process form the tripartite synapse. (6) In the tripartite synapse, communication between the neurons and astrocytes occur at different levels, but especially in the glutamate metabolism. (8)??This review discusses if alterations in astrocyte-neuron interactions at tripartite synapses in the prefrontal cortex promote the onset of MDD.