Adenosine A2A Receptors Shut Down Adenosine A1 Receptor-Mediated Presynaptic Inhibition to Promote Implementation of Hippocampal Long-Term Potentiation

by Selleckchem | Jul 18 2023

Adenosine operates a modulation system fine-tuning the efficiency of synaptic transmission and plasticity through A1 and A2A receptors (A1R, A2AR), respectively. Supramaximal activation of A1R can block hippocampal synaptic transmission, and the tonic engagement of A1R-mediated inhibition is increased with increased frequency of nerve stimulation. This is compatible with an activity-dependent increase in extracellular adenosine in hippocampal excitatory synapses, which can reach levels sufficient to block synaptic transmission. We now report that A2AR activation decreases A1R-medated inhibition of synaptic transmission, with particular relevance during high-frequency-induced long-term potentiation (LTP). Thus, whereas the A1R antagonist DPCPX (50 nM) was devoid of effects on LTP magnitude, the addition of an A2AR antagonist SCH58261 (50 nM) allowed a facilitatory effect of DPCPX on LTP to be revealed. Additionally, the activation of A2AR with CGS21680 (30 nM) decreased the potency of the A1R agonist CPA (6-60 nM) to inhibit hippocampal synaptic transmission in a manner prevented by SCH58261. These observations show that A2AR play a key role in dampening A1R during high-frequency induction of hippocampal LTP. This provides a new framework for understanding how the powerful adenosine A1R-mediated inhibition of excitatory transmission can be controlled to allow the implementation of hippocampal LTP.

Comments:

The passage you provided describes the modulation system of adenosine in synaptic transmission and plasticity in the brain, specifically in the hippocampus. Adenosine acts through two types of receptors: A1 receptors (A1R) and A2A receptors (A2AR).

The activation of A1R can effectively block synaptic transmission in the hippocampus when it is supramaximally activated. This means that when adenosine levels are high, A1R can inhibit the transmission of signals between neurons. The engagement of A1R-mediated inhibition is increased with higher frequencies of nerve stimulation. This suggests that increased neuronal activity leads to higher levels of extracellular adenosine, which in turn can block synaptic transmission.

However, the passage introduces the role of A2AR in modulating the effects of A1R. The activation of A2AR actually decreases the A1R-mediated inhibition of synaptic transmission. This becomes particularly relevant during high-frequency-induced long-term potentiation (LTP), which is a cellular mechanism associated with learning and memory.

The passage further explains that when the A1R antagonist DPCPX is administered alone, it does not have any significant effects on the magnitude of LTP. However, when an A2AR antagonist, SCH58261, is added along with DPCPX, the inhibitory effects of A1R are reduced, resulting in a facilitatory effect on LTP.

In addition, the activation of A2AR using the agonist CGS21680 reduces the potency of the A1R agonist CPA to inhibit synaptic transmission in the hippocampus. This effect of A2AR activation can be blocked by SCH58261.

Overall, these observations suggest that A2AR plays a crucial role in dampening the inhibitory effects of A1R during high-frequency-induced LTP in the hippocampus. This interaction between A1R and A2AR provides a new understanding of how adenosine modulation can control the inhibitory transmission in order to allow the implementation of LTP, which is important for learning and memory processes.