Role of Astrocyte-Derived ATP Signaling in the Dopamine Circuit and Major Depression.

Major depressive disorder (MDD) is a common but serious mental illness that negatively affects emotion, cognition, physical activity, and increases mortality. In general, the manifestation of depression is thought to be due to the imbalance of neurotransmitters in the brain. These neurotransmitters include glutamate, GABA, and especially a class of monoamines, such as serotonin, dopamine, and norepinephrine. Many recent studies have demonstrated the importance of dopamine homeostasis and dynamics on reward and motivation especially after exposure to chronic stress. Our previous studies have identified a novel astrocyte-dependent modulatory mechanism for the dopamine system, by which the hormone insulin regulates ATP release in astrocytes to modulate dopamine release and depressive-like behavior in mice. These exciting findings provide a novel and potentially important molecular basis for the etiology of depressive disorders, particularly in the context of diabetes and insulin resistance. How insulin mediates astrocytic ATP release has yet to be elucidated, although exocytosis from secretory lysosomes has been suggested as a major route of ATP release by astrocytes. In this project, we aim to further investigate the molecular mechanism and functional relevance of the astrocytic insulin action and ATP release on dopaminergic signaling under chronic stress. We hypothesize that insulin regulates the exocytosis of ATP from secretory lysosomes in astrocytes to contribute to dopamine release, and impairment of this astrocyte-initiated pathway will negatively impact dopamine release and exacerbate deficits in reward in mice exposed to chronic mild stress. To test this central hypothesis, we have developed a new genetic mouse model, in which we can specifically delete astrocytic vesicular nucleotide transporters (VNUTs) that are required for loading ATP into secretory lysosomes. This project is currently funded by an NIH R01 grant (MH125903).