ACTIVITY-DEPENDENT RELEASE OF ENDOGENOUS ADENOSINE MODULATES SYNAPTICRESPONSES IN THE RAT HIPPOCAMPUS

Adenosine is a potent inhibitory modulator of synaptic transmission in the CNS, but its role in normal physiological function is unclear. In the present experiments, we have found electrophysiological evidence for activity-dependent release of adenosine from hippocampal slices ev oked by physiologically relevant stimulation, and have demonstrated th at this adenosine modifies synaptic activity in this brain region. Whe n two independent excitatory pathways to the CA1 pyramidal neurons are used to evoke field EPSP responses, prior activation of one pathway w ill inhibit the EPSP evoked via the other input. This inhibition can b e antagonized by the nonselective adenosine receptor antagonist theoph ylline, and by the selective A1 receptor antagonist 8-cyclopentyltheop hylline, suggesting that the inhibitory response is due to the release of endogenous adenosine that activates presynaptic release-modulating A1 receptors. This inhibition can be observed following a single stim ulus to the conditioning pathway, although it is more pronounced when a train of conditioning pulses is used, and is maximal following a tra in of 16-32 stimuli (at 100 Hz). When a train of four conditioning pul ses is used, the inhibition appears with a latency of approximately 50 msec, peaks approximately 200-250 msec following the conditioning tra in, and recovers to baseline between 1 and 2 sec. Further evidence tha t this inhibition of excitatory transmission is mediated via adenosine is provided by the observation that superfusion with dipyridamole (an adenosine uptake inhibitor), and the adenosine deaminase inhibitor er ythro-(2-hydroxy-3-non-yl)adenine, enhanced both the duration and ampl itude of the inhibition. These results suggest that endogenous adenosi ne concentrations at the presynaptic nerve terminals of Schaffer colla teral and commissural afferents to the CA1 region can be rapidly incre ased by activation of nearby synapses, and that this adenosine is quic kly cleared from the extracellular space by uptake and/or deamination.