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Volume 16, Number 18, Issue of September 15, 1996 pp. 5603-5612
Copyright ©1996 Society for Neuroscience

Modulation of Excitatory Synaptic Transmission by Adenosine Released from Single Hippocampal Pyramidal Neurons

Received April 16, 1996; revised June 14, 1996; accepted June 26, 1996.

James M. Brundege¹ and Thomas V. Dunwiddie^{1, 2}

¹ Department of Pharmacology, University of Colorado Health Sciences Center, and ² Program in Neuroscience, University of Colorado Health Sciences Center, and Veterans Administration Medical Research Service, Denver, Colorado 80262

Adenosine is a potent neuromodulator in the CNS, but the mechanisms that regulate adenosine concentrations in the extracellular space remain unclear. The present study demonstrates that increasing the intracellular concentration of adenosine in a single hippocampal CA1 pyramidal neuron selectively inhibits the excitatory postsynaptic potentials in that cell. Loading neurons with high concentrations of adenosine via the whole-cell patch-clamp technique did not affect the GABA_A-mediated inhibitory postsynaptic potentials, the membrane resistance, or the holding current, whereas it significantly increased the adenosine receptor-mediated depression of excitatory postsynaptic currents. The effects of adenosine could not be mimicked by an agonist at the intracellular adenosine P-site, but the effects could be antagonized by a charged adenosine receptor antagonist and by adenosine deaminase, demonstrating that the effect was mediated via adenosine acting at extracellular adenosine receptors. The effect of adenosine loading was not blocked by BaCl₂ and therefore was not caused by an adenosine-activated postsynaptic potassium conductance. Adenosine loading increased the paired-pulse facilitation ratio, demonstrating that the effect was mediated by presynaptic adenosine receptors. Finally, simultaneous extracellular field recordings demonstrated that the increase in extracellular adenosine was confined to excitatory synaptic inputs to the loaded cell. These data demonstrate that elevating the intracellular concentration of adenosine in a single CA1 pyramidal neuron induces the release of adenosine into the extracellular space in such a way that it selectively inhibits the excitatory inputs to that cell, and the data support the general conclusion that adenosine is a retrograde messenger used by pyramidal neurons to regulate their excitatory input.

Key words: adenosine; synaptic modulation; hippocampus; adenosine transport; A1 receptors; fEPSP; electrophysiology; whole-cell recording

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