title: Adenosine A(2A) Receptors as novel upstream regulators of BDNF-mediated attenuation of hippocampal Long-Term Depression (LTD).
abstract: Hippocampal Long-Term Potentiation (LTP) is facilitated by BDNF, through the activation of tropomyosin-related kinase B (TrkB) receptors. However, an influence of BDNF upon Long-Term Depression (LTD) was also shown. The present work aimed to further evaluate the effect of BDNF and TrkB receptors upon CA1 hippocampal LTD and to elucidate whether this effect is under the upstream control of other signalling processes, such as the adenosine A(2A)Receptors (A(2A)Rs). LTD, induced by a Low-Frequency Stimulation (LFS, 900 pulses, 1 Hz) in the CA1 area of rat hippocampal slices, was significantly attenuated when these slices were exposed to BDNF (60-100 ng/mL). A lower BDNF concentration (20 ng/ml) was only effective to inhibit LTD if A(2A)Rs were activated by a selective agonist, CGS 21680 (10 nM), or if the extracellular adenosine level was increased by 5-iodotubercidin (100 nM). BDNF (100 ng/ml) effect upon LTD was prevented by K252a (200 nM), which is known to prevent TrkB transphosphorylation, hence suggesting that this action requires TrkB receptor activation. BDNF (100 ng/ml) lacked effect on an adenosine-depleted background (adenosine deaminase, 2 U/ml) or under selective A(2A)R blockade (SCH 58261, 100 nM), indicating that it relies on tonic A(2A)R activation. Forskolin (10 μM), a cell-permeable activator of adenylate cyclase, rescued BDNF (100 ng/ml) effect in slices where A(2A)Rs were blocked with SCH 58261 (100 nM), whereas a PKA inhibitor, H-89 (1 μM), prevented LTD attenuation by BDNF (100 ng/ml). We conclude that the influence of BDNF TrkB receptors upon LTD is under the strict control of A(2A)Rs activation, through a mechanism that requires the cAMP/PKA transducing system.
authors.affiliation: Institute of Pharmacology and Neurosciences, Faculty of Medicine, University of Lisbon, Lisbon, Portugal; Unit of Neurosciences, Institute of Molecular Medicine, University of Lisbon, Lisbon, Portugal.
authors.forename: Tiago M
authors.initials: TM
authors.lastname: Rodrigues
authors.affiliation: Institute of Pharmacology and Neurosciences, Faculty of Medicine, University of Lisbon, Lisbon, Portugal; Unit of Neurosciences, Institute of Molecular Medicine, University of Lisbon, Lisbon, Portugal.
authors.forename: André
authors.initials: A
authors.lastname: Jerónimo-Santos
authors.affiliation: Institute of Pharmacology and Neurosciences, Faculty of Medicine, University of Lisbon, Lisbon, Portugal; Unit of Neurosciences, Institute of Molecular Medicine, University of Lisbon, Lisbon, Portugal.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Sebastião
authors.affiliation: Institute of Pharmacology and Neurosciences, Faculty of Medicine, University of Lisbon, Lisbon, Portugal; Unit of Neurosciences, Institute of Molecular Medicine, University of Lisbon, Lisbon, Portugal. Electronic address: diogenes@fm.ul.pt.
authors.forename: Maria José
authors.initials: MJ
authors.lastname: Diógenes
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D058908:Adenosine A2 Receptor Agonists / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology; D000243:Adenosine Deaminase / Q000378:metabolism; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005110:Extracellular Space / Q000378:metabolism; D066298:In Vitro Techniques; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology*; D010627:Phenethylamines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D020813:Receptor, trkB / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology
chemical_list: C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D019208:Brain-Derived Neurotrophic Factor; D004791:Enzyme Inhibitors; D010627:Phenethylamines; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; D014230:Triazoles; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D020813:Receptor, trkB; D017868:Cyclic AMP-Dependent Protein Kinases; D000243:Adenosine Deaminase; D000262:Adenylyl Cyclases; D000241:Adenosine
keywords: Adenosine A(2A) Receptor; Brain-Derived Neurotrophic Factor; Hippocampus; Long Term Depression