The syncytiopathy hypothesis of depression: downregulation of glial connexins may protract synaptic information processing and cause memory impairment.

Astrocytes interconnected via gap junctions build an astrocytic syncytium. Gap junctions are composed of connexin proteins that are activated by substances of the neuronal system. It is hypothesized that disorders in the astrocytic syncytium may represent a main component of the pathophysiology of depression, called syncytiopathy. If the expression of connexin proteins is downregulated, a compensatory upregulation of astrocytic receptors may occur leading to an overproduction of these. Such an excess of astrocytic receptors exerts an imbalance of synaptic neurotransmission, because of a relative lack of neurotransmitters for the occupancy of astrocytic receptors so that neurotransmission is protracted. This delay of information processing may be responsible for the main symptoms of depression. In addition, the downregulation of connexin expression may also lead to an incomplete syncytium formation, responsible for memory impairment in severe depression. Finally, general approaches for testing the hypothesis are outlined.