Modulation of gamma oscillations by endogenous adenosine through A1 and A2A receptors in the mouse hippocampus

Adenosine serves as a homeostatic factor, regulating hippocampal activity through A1 receptor-mediated inhibition. Gamma frequency oscillations, associated with cognitive functions, emerge from increased network activity. Here we test the hypothesis that hippocampal gamma oscillations are modulated by ambient adenosine levels.In mouse hippocampal slices exogenous adenosine suppressed the power of both kainate-induced gamma oscillations and spontaneous gamma oscillations, observed in a subset of slices in normal aCSF. Kainate-induced gamma oscillation power was suppressed by the A1 receptor agonist PIA and potentiated by the A1 receptor antagonist 8-CPT to three times matched control values with an EC50 of 1.1 μM. 8-CPT also potentiated spontaneous gamma oscillation power to five times control values. The A2A receptor agonist CGS21680 potentiated kainate-induced gamma power to two times control values (EC50 0.3 nM), but this effect was halved in the presence of 8-CPT. The A2A receptor antagonist ZM241385 suppressed kainate-induced gamma power. The non-selective adenosine receptor antagonist caffeine induced gamma oscillations in slices in control aCSF and potentiated both kainate-induced gamma and spontaneous gamma oscillations to three times control values (EC50 28 μM).Decreasing endogenous adenosine levels with adenosine deaminase increased gamma oscillations. Increasing endogenous adenosine levels with the adenosine kinase inhibitor 5-iodotubericidin suppressed gamma oscillations. Partial hypoxia-induced suppression of gamma oscillations could be prevented by 8-CPT.These observations indicate that gamma oscillation strength is powerfully modulated by ambient levels of adenosine through A1 receptors, opposed by A2A receptors. Increased gamma oscillation strength is likely to contribute to the beneficial cognitive effects of caffeine.