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This Article Full Text Full Text (PDF) All Versions of this Article: 102/3/1984    most recent 90695.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (1) Google Scholar Articles by Dulla, C. G. Articles by Masino, S. A. PubMed PubMed Citation Articles by Dulla, C. G. Articles by Masino, S. A.

Intracellular Acidification Causes Adenosine Release During States of Hyperexcitability in the Hippocampus

¹Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California; ²Department of Biological Sciences, University of Warwick, Coventry, United Kingdom; ³Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; and ⁴Neuroscience Program and Department of Psychology, Trinity College, Hartford, Connecticut

Submitted 19 June 2008; accepted in final form 8 July 2009

Abstract

Decreased pH increases extracellular adenosine in CNS regions as diverse as hippocampus and ventral medulla. However, thus far there is no clear consensus whether the critical pH change is a decrease in intracellular and/or extracellular pH. Previously we showed that a decrease in extracellular pH is necessary and a decrease in intracellular pH alone is not sufficient, to increase extracellular adenosine in an acute hippocampal slice preparation. Here we explored further the role of intracellular pH under different synaptic conditions in the hippocampal slice. When synaptic excitability was increased, either during -aminobutyric acid type A receptor blockade in CA1 or after the induction of persistent bursting in CA3, a decrease in intracellular pH alone was now sufficient to: 1) elevate extracellular adenosine concentration, 2) activate adenosine A₁ receptors, 3) decrease excitatory synaptic transmission (CA1), and 4) attenuate burst frequency in an in vitro seizure model (CA3). Hippocampal slices obtained from adenosine A₁ receptor knockout mice did not exhibit these pH-mediated effects on synaptic transmission, further confirming the role of adenosine acting at the adenosine A₁ receptor. Taken together, these data strengthen and add significantly to the evidence outlining a change in pH as an important stimulus influencing extracellular adenosine. In addition, we identify conditions under which intracellular pH plays a dominant role in regulating extracellular adenosine concentrations.