A3 adenosine receptor regulates depression-like behaviors through astrocyte-nourished excitatory synapse formation

Abnormal excitatory synaptic function plays a critical role in major depressive disorder. In this study, we investigated the role of the A 3 adenosine receptor (A 3 AR), previously implicated in affective disorders, in excitatory synapse formation within prefrontal cortical circuits. Using a corticosterone-induced mouse model of depression, we found that the adenosine receptor activator 3′-deoxyadenosine (3′dA) produced antidepressant-like effects and selectively increased A 3 AR expression, whereas fluoxetine did not. 3′dA also restored the synaptic organizers neuroligin-2 (NLGN2) and neurexin-2 and elevated BDNF, excitatory synaptic markers (synapsin-1, PSD-95, and GluR1), and dendritic spine density in the PFC. Notably, enhanced NLGN2 immunoreactivity co-localized with astrocytes exclusively in 3′dA-treated mice but not in fluoxetine-treated mice. Pharmacological blockade of A 3 AR with MRS-1191 prevented the 3′dA-induced behavioral and molecular changes in this corticosterone-induced depressive-like mouse model. Together, our findings identify A 3 AR as a key regulator of NLGN2 expression and excitatory synapse formation and suggest a potential target for antidepressant therapies.