グリアのプリン作動性シグナルとうつ病

抄録

The molecular pathogenesis of depression is often explained by the catecholaminetheory. However, there are many cases of so-called refractory depression thatare resistant to existing noradrenergic and serotonin activating drugs, so thetrue molecular pathogenesis of depression needs to be elucidated. Asdemonstrated by Prof Burnstock, ATP is not a merely energy currency but is animportant intercellular signaling molecule that mediates information betweenneurons and glial cells in the central nervous system. Animal studies havereported that "ATP" is the most universally altered intercellular signalingmolecule in depressive symptoms, and that a decrease in this extracellular ATPcauses depressive symptoms (Nat Med 2013). However, its molecular and regulatorymechanisms remain unclear. In the present study, we tested this ATP hypothesisand elucidated the molecular mechanism of this ATP hypothesis using fluoxetine(FLX), a typical SSRI antidepressant, which increased extracellular ATP (ATPo)in the hippocampal brain in a dose-dependent manner. This ATPo increase wasdependent on astrocytes rather than neurons, and the molecular mechanism of thisincrease was found to be an enhancement of the ATP exocytosis. We found thatreleased ATP acts as ATP and degraded adenosine on P2Y11 and A2b receptors,respectively, to enhance the cAMP-CREB system and that this signal enhancementleads to BDNF expression. Very interestingly, the sequence of responses fromATP/adenosine to BDNF production was induced in astrocytes, but not in neurons.We further discuss the importance of astrocytes as a prime target fordepression.