Enhancement of long-term potentiation by brain-derived neurotrophic factor requires adenosine A2A receptor activation by endogenous adenosine

The excitatory action of brain-derived neurotrophic factor (BDNF) on synaptic transmission is triggered by adenosine A(2A) receptor activation. Since high-frequency neuronal firing, such as that inducing long-term potentiation (UP), favours both A(2A) receptor activation and BDNF effects on transmission, we now evaluated the influence of adenosine on the facilitatory action of BDNF upon CA1 hippocampal UP. theta-Burst stimulation of the pyramidal inputs induced a significant and persistent increase in field EPSP slopes, and this potentiation was augmented in the presence of BDNF (20 ng/ml), an action prevented by the inhibitor of Trk receptor autophosphorylation, K252a (200 nM). Removal of endogenous extracellular adenosine with adenosine deaminase (ADA, 1 U/ml), as well as the antagonism of adenosine A(2A) receptors with SCH58261 (100 nM), prevented the excitatory action of BDNF upon LTR In an adenosine depleted background (with ADA), activation of adenosine A(2A) receptors (with 10 nM CGS21680) restored the facilitatory effect of BDNF on LTP; this was fully prevented by the protein kinase A inhibitor, H-89 (1 mu M) and mimicked by the adenylate cyclase activator, forskolin (10 mu M). In similar experiments, activation of adenosine inhibitory A(1) receptors (with 5 nM CPA) did not affect the facilitatory effect of BDNF. In conclusion, the facilitatory action of BDNF upon hippocampal UP is critically dependent on the presence of extracellular adenosine and A(2A) receptor activation through a cAMP/PKA-dependent mechanism. Since extracellular adenosine accumulates upon high-frequency neuronal firing, the present results reveal a key process to allow the influence of BDNF upon synaptic plasticity. (C) 2008 Elsevier Ltd. All rights reserved.