Adenosine A1 receptors presynaptically modulate excitatory synaptic input onto subiculum neurons

Adenosine is an endogenous neuromodulator previously shown to suppress synaptic transmission and membrane excitability in the CNS. In this study we have determined the actions of adenosine on excitatory synaptic transmission in the subiculum, the main output area for the hippocampus. Adenosine (10 μM) reversibly inhibited excitatory post synaptic currents (EPSCs) recorded from subiculum neurons. These actions were mimicked by the A1 receptor-specific agonist, N6-cyclopentyl-adenosine (CPA, 10 nM) and blocked by the A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 500 nM), but were unaffected by the A2A antagonist ZM 241385 (50 nM). In membrane excitability experiments, bath application of adenosine and CPA reversibly inhibited action potentials (AP) in subiculum neurons that were evoked by stimulation of the pyramidal cell layer of the CA1, but not by depolarizing current injection steps in subiculum neurons, suggesting a presynaptic mechanism of action. In support, adenosine and CPA application reduced mEPSC frequency without modulating mEPSC amplitude. These studies suggest that modulation of subiculum neuron excitability by adenosine is mediated via presynaptic A1 receptors.