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

Abstract

Summary Abnormal excitatory synaptic function plays a critical role in major depressive disorder. In this study, we investigated the role of the A3 adenosine receptor (A3AR), 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 A3AR 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 A3AR with MRS-1191 prevented the 3′dA-induced behavioral and molecular changes in this corticosterone-induced depressive-like mouse model. Together, our findings identify A3AR as a key regulator of NLGN2 expression and excitatory synapse formation and suggest a potential target for antidepressant therapies.