Adenosine A1 antagonism increases specific synaptic forms of glutamate release during anoxia, revealing a unique source of excitation.
The role of the adenosine A1 receptor in the modulation of anoxia-induced synaptic glutamate release was examined in CA1 pyramidal neurons by whole-cell voltage-clamp recording in the rat hippocampal slice preparation. Anoxia leads to an increased action potential-independent synaptic glutamate release in the form of a higher frequency of miniature excitatory postsynaptic currents (mEPSCs). This increase is not significantly affected when slices are preincubated in the adenosine A1 receptor antagonist, 8-cyclopentyl-1, 3-dipropylxanthine (DPCPX). A second population of spontaneous inward currents, however, occurs in DPCPX-treated slices during a well-defined period following the onset of anoxia. Their suppression by glutamate antagonists, tetrodotoxin, or by the cutting of the Schaffer collateral pathway indicates that they represent action potential-dependent, glutamatergic excitatory postsynaptic currents (ap-EPSCs) originating from CA3 pyramidal neurons. CA3 neurons were examined in current-clamp whole-cell patch mode to determine the origin of this increased orthodromic excitation. After the onset of anoxia, CA3 cells initially exhibit a small depolarization or hyperpolarization associated with a decrease in input resistance. This is followed by transient depolarization (the depolarizing "nub"), which is associated with an increase in input resistance. The nub evoked single as well as bursts of action potentials in CA3 neurons. The occurrence of these CA3 nub-elicited action potentials coincides with that of ap-EPSCs recorded in the CA1 cells. Recording with cesium- rather than standard potassium-containing electrodes results in the suppression of the nub and its associated increase in input resistance. In conclusion we have shown that adenosine tone plays an important role in suppressing anoxia-induced spontaneous ap-EPSCs but not action potential-independent mEPSCs in CA1 neurons. These EPSCs originate from a depolarization in CA3 pyramidal neurons, which is associated with an increase in resistance. This previously undescribed phenomenon likely results from a decrease in the conductance of an unidentified potassium channel.
Katchman
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Department of Neurology, Georgetown University Medical Center, Washington, D.C. 20007, USA.
Hershkowitz
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D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D004594:Electrophysiology; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002534:Hypoxia, Brain / Q000378:metabolism*; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism; D008297:Male; D018408:Patch-Clamp Techniques; D058915:Purinergic P1 Receptor Antagonists; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*; D013779:Tetrodotoxin / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology
D007473:Ion Channels; D058915:Purinergic P1 Receptor Antagonists; D014970:Xanthines; D018698:Glutamic Acid; D013779:Tetrodotoxin; C051360:1,3-dipropyl-8-cyclopentylxanthine