Adenosine A_2A Receptor Agonist PSB-0777 Modulates Synaptic Proteins and AMPA Receptor Expression in A Dose- and Time-Dependent Manner in Rat Primary Cortical Neurons

Abstract

Regulating synaptic formation and transmission is critical for the physiology and pathology of psychiatric disorders. The adenosine A_2A receptor subtype has attracted widespread attention as a key regulator of neuropsychiatric activity, neuroprotection and injury. In this study, we systematically investigated the regulatory effects of a novel A_2A receptor agonist, PSB-0777, on the expression of synaptic proteins and AMPA receptors at the cellular level in a time- and dose-dependent manner. After 30 minutes of high-dose PSB-0777 stimulation, the expression of Syn-1, PSD95, and AMPA receptors and the number of synapses were rapidly and significantly increased in rat primary cortical neurons compared with the control. Sustained elevation was found in the low and medium-dose groups after 24 hours and 3 days of treatment. In contrast, after stimulation with PSB-0777 for 3 consecutive days, the expression of Syn-1 was decreased, and PSD95, AMPA receptors and the number of synapses were no longer increased in the high-dose group. Our study focuses on the detailed and systematic regulation of synaptic proteins and AMPA receptors by an A_2A receptor agonist, PSB-0777, which may result in both beneficial and detrimental effects on neurotransmission and neuroprotection and may contribute to the pathophysiology of psychiatric disorders related to A_2A receptors. These experimental data may contribute to understanding of the mechanisms for neuroprotective and therapeutic effect of A_2A receptor agonists.