Lateral septum adenosine A2A receptors control stress-induced depressive-like behaviors via signaling to the hypothalamus and habenula

Abstract Depression is the single largest contributor to the burden of disease, yet the current antidepressant medications are limited by high non-responsiveness and significant side effects. The lateral septum (LS) is thought to control of depression, however, the cellular and circuit substrates are largely unknown. Here, we identified a subpopulation of LS GABAergic adenosine A2A receptors (A2AR)-positive neurons mediating depression via direct projects to the lateral habenula (LHb) and the hypothalamus. Activation of A2AR in the LS augmented the spiking frequency of A2AR-positive neurons leading to a decreased activation of surrounding neurons. Accordingly, modulation of LS-A2AR-positive neurons activity via optogenetic stimulation formatted depressive-like phenotype and the optogenetic activation of LS-A2AR-positive neurons projection terminals to the LHb or the hypothalamus, phenocopied depressive behaviors. Moreover, we shown a selective upregulation of A2AR in the LS in two mouse models of repeated stress-induced depression and in postmortem brains of suicide completers suffered from depression disorder, and the bi-directional manipulation of LS-A2AR activity demonstrated that LS-A2ARs are necessary and sufficient to trigger depressive phenotypes. This identification that aberrantly increased A2AR signaling in the LS is a critical upstream regulator of repeated stress-induced depressive-like behaviors provides a neurophysiological and circuit-based justification of the antidepressant potential of A2AR antagonists, prompting their clinical translation.