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The Journal of Neuroscience, March 24, 2004, 24(12):2905-2913; doi:10.1523/JNEUROSCI.4454-03.2004

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Development/Plasticity/Repair
Activation of Adenosine A_2A Receptor Facilitates Brain-Derived Neurotrophic Factor Modulation of Synaptic Transmission in Hippocampal Slices

Maria José Diógenes,¹ Catarina Cunha Fernandes,¹ Ana Maria Sebastião,¹ and Joaquim Alexandre Ribeiro^1,2

¹Laboratory of Neurosciences and ²Institute of Pharmacology, Institute of Molecular Medicine, Faculty of Medicine, University of Lisbon, 1649-028 Lisbon, Portugal

Both brain-derived neurotrophic factor (BDNF) and adenosine influence neuronal plasticity. We now investigated how adenosine influences the action of BDNF on synaptic transmission in the CA1 area of the rat hippocampal slices. Alone, BDNF (20–100 ng/ml) did not significantly affect field EPSPs (fEPSPs). However, a 2 min pulse of high-K⁺ (10 mM) 46 min before the application of BDNF (20 ng/ml) triggered an excitatory action, an effect blocked by the TrkB receptor inhibitor K252a (200 nM), by the adenosine A_2A receptor antagonist ZM 241385 (50 nM), and by the protein kinase A inhibitor H-89 (1 µM). Presynaptic, rather than postsynaptic depolarization was required to trigger the BDNF action because after K⁺ depolarization BDNF also increased EPSCs recorded from pyramidal neurons voltage-clamped at –60 mV, and transient postsynaptic depolarization was unable to unmask the BDNF action. A weak theta burst stimulation of the afferents could elicit potentiation of synaptic transmission only when applied in the presence of BDNF. Activation of adenosine A_2A receptors with CGS 21680 (10 nM), or the increase in extracellular adenosine levels induced by 5-iodotubercidin (100 nM) triggered the excitatory action of BDNF, a process prevented by ZM 241385 and by H-89. In the presence of dibutyryl-cAMP (0.5 mM), BDNF also increased fEPSPs but postsynaptic cAMP (0.5 mM) was unable to trigger the BDNF action.

It is concluded that presynaptic activity-dependent release of adenosine, through activation of A_2A receptors, facilitates BDNF modulation of synaptic transmission at hippocampal synapses.

Key words: adenosine receptors; BDNF; hippocampus; synaptic transmission; neuromodulation; neurotrophic factors

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Received June 2, 2003; revised January 20, 2004; accepted January 20, 2004.

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