Li_2026_iScience_29_116843

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.