Astrocytes and major depression: The purinergic avenue

Major depressive disorder (MDD) is one of the most prevalent psychiatric illnesses worldwide which impairs the social functioning of the afflicted patients. Astrocytes promote homeostasis of the CNS and provide defense against various types of harmful influences. Increasing evidence suggests that the number, morphology and function of astrocytes are deteriorated in the depressed brain and the malfunction of the astrocytic purinergic system appears to participate in the pathophysiology of MDD. Adenosine 5'-triphosphate (ATP) released from astrocytes modulates depressive-like behavior in animal models and probably also clinical depression in patients. Astrocytes possess purinergic receptors, such as adenosine A_2A receptors (Rs), and P2X7, P2Y₁, and P2Y₁₁Rs, which mediate neuroinflammation, neuro(glio)transmission, and synaptic plasticity in depression-relevant areas of the brain (e.g. medial prefrontal cortex, hippocampus, amygdala nuclei). By contrast, astrocytic A₁Rs are neuroprotective and immunosuppressive. In the present review, we shall discuss the release of purines from astrocytes, and the expression/function of astrocytic purinergic receptors. Subsequently, we shall review in more detail novel evidence indicating that the dysregulation of astrocytic purinergic signaling actively contributes to the pathophysiology of depression and shall discuss possible therapeutic options based on knowledge recently acquired in this field.