Activation of Adenosine A2A Receptor Facilitates Brain-Derived Neurotrophic Factor Modulation of Synaptic Transmission in Hippocampal Slices (original) (raw)
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Journal of Neurochemistry, 2007
Brain-derived neurotrophic factor (BDNF) is an endogenous glycoprotein belonging to neurotrophins, a family of signaling molecules which play a key role in regulating neuronal proliferation, differentiation and survival (Huang and Reichardt 2001; Vicario-Abejón et al. 2002; Kalb 2005). Among the neurotrophins, BDNF has the widest distribution in the central nervous system, where it is mostly expressed in the cerebral cortex and the hippocampus (Schmidt-Kastner et al. 1996; Conner et al. 1997). In the adult hippocampus, BDNF is critically involved in the regulation of synaptic plasticity (Lu 2003) and facilitates long-term potentiation (LTP)
Neuroscience, 2002
AbstractöAdenosine tonically inhibits synaptic transmission through actions at A 1 receptors. It also facilitates synaptic transmission, but it is unclear if this facilitation results from pre-and/or postsynaptic A 2A receptor activation or from indirect control of inhibitory GABAergic transmission. The A 2A receptor agonist, CGS 21680 (10 nM), facilitated synaptic transmission in the CA1 area of rat hippocampal slices (by 14%), independent of whether or not GABAergic transmission was blocked by the GABA A and GABA B receptor antagonists, picrotoxin (50 WM) and CGP 55845 (1 WM), respectively. CGS 21680 (10 nM) also inhibited paired-pulse facilitation by 12%, an e¡ect prevented by the A 2A receptor antagonist, ZM 241385 (20 nM). These e¡ects of CGS 21680 (10 nM) were occluded by adenosine deaminase (2 U/ml) and were made to reappear upon direct activation of A 1 receptors with N 6 -cyclopentyladenosine (CPA, 6 nM). CGS 21680 (10 nM) only facilitated (by 17%) the K þ -evoked release of glutamate from superfused hippocampal synaptosomes in the presence of 100 nM CPA. This e¡ect of CGS 21680 (10 nM), in contrast to the isoproterenol (30 WM) facilitation of glutamate release, was prevented by the protein kinase C inhibitors, chelerythrine (6 WM) and bisindolylmaleimide (1 WM), but not by the protein kinase A inhibitor, H-89 (1 WM). Isoproterenol (30 WM), but not CGS 21680 (10^300 nM), enhanced synaptosomal cAMP levels, indicating that the CGS 21680-induced facilitation of glutamate release involves a cAMP-independent protein kinase C activation. To discard any direct e¡ect of CGS 21680 on adenosine A 1 receptor, we also show that in autoradiography experiments CGS 21680 only displaced the adenosine A 1 receptor antagonist, 1,3dipropyl-8-cyclopentyladenosine ([ 3 H]DPCPX, 0.5 nM) with an EC 50 of 1 WM in all brain areas studied and CGS 21680 (30 nM) failed to change the ability of CPA to displace DPCPX (1 nM) binding to CHO cells stably transfected with A 1 receptors.
Adenosine A2 receptors modulate hippocampal synaptic transmission via a cyclic-AMP-dependent pathway
Neuroscience, 1998
Blockade of adenosine A 2 receptors has been shown to significantly reduce the level of tetanus-induced long-term potentiation in area CA1 of rat hippocampus [Kessey K. et al. (1997) Brain Res. 756, 184-190;) Biochem. biophys. Res. Commun. 181, 1010-1014. In the present study, the effects of A 2 receptor activation and blockade on the modulation of normal synaptic transmission and tetanus-induced long-term potentiation were examined at the Schaffer-CA1 synapse in rat hippocampal slices. A 2 receptor activation reversibly enhanced synaptic transmission evoked by low-frequency test pulses as measured by the dendritic field excitatory postsynaptic potential. In the presence of A 1 receptor blockade, A 2 activation further enhanced the excitatory postsynaptic potential, while A 2 receptor blockade resulted in a reversible decrease of the excitatory postsynaptic potential. The A 2a receptor agonist, CGS21680, had no effect on the excitatory postsynaptic potential, suggesting that tonic activation of A 2b receptors contributes to synaptic transmission under normal physiological conditions. Furthermore, we investigated the contribution of A 2 receptors to the level of tetanus-induced long-term potentiation. Under control conditions, a single tetanus potentiated the excitatory postsynaptic potential by 63.5% relative to baseline 30 min post-tetanus. In contrast, tetanus-induced long-term potentiation during A 2 blockade was 21.3%. A 2 receptor activation increased the level of tetanus-induced long-term potentiation to 90.2%. Because A 2 receptors are known to stimulate cyclic-AMP accumulation, the possible involvement of cyclic-AMP was examined. Forskolin, a direct adenylate cyclase activator, and 8-bromo-cyclic-AMP, a membrane-permeable analog of cyclic-AMP, were able to reconstitute tetanusinduced long-term potentiation during A 2 receptor blockade; however, the inactive analog 1,9-dideoxyforskolin had no effect, indicating that the effects of A 2 activation on synaptic transmission were mediated largely through the regulation of intracellular cyclic-AMP.
The Journal of physiology, 1985
The effect of adenosine on paired synaptic responses was characterized in the CA1 region of the rat hippocampus in vitro. Adenosine increased the degree of synaptic facilitation at a 40 ms conditioning-testing interval under all conditions tested. Even when the stimulation intensity was increased so as to counteract the direct depressant effect of adenosine on synaptic transmission, its effect on facilitation was maintained. The ability of adenosine to increase synaptic facilitation was a complex function of several variables. The effect was enhanced by increasing the calcium concentration of the medium, and was most pronounced at short conditioning-testing intervals and at low response amplitudes. Adenosine was particularly efficacious in blocking the depression of synaptic responses observed in high-calcium medium at short conditioning-testing intervals. Because this depression most probably reflects depletion of the available store of releasable transmitter, one mechanism by whic...
A role for adenosine A receptors in the induction of long-term potentiation
1997
Although reductions in neurotransmission have been reported in response to agonist-mediated adenosine A receptor activation, the 1 implications of A receptor activation on synaptic transmission have not been well explored. We examined the role adenosine A 2 2 receptors play in the efficacy of neurotransmission between the Schaffer collateral-CA1 pathway in the rat transverse hippocampal slice. A receptor blockade in the presence of complete A receptor inhibition led to a reversible reduction of the field excitatory post-synaptic 2 1 Ž . Ž . potential EPSP slope in response to low-frequency test pulses 0.033 Hz indicating that A receptors can enhance synaptic 2 Ž . transmission. A receptor blockade by the A antagonist, DMPX 3,7-dimethyl-1-propargylxanthine prevented the induction of 2 2 Ž . tetanus-induced long-term potentiation LTP of the EPSP. In contrast, no such effect on LTP induction was observed during A receptor 1 blockade. We also examined the effects of DMPX on the inductio...
British Journal of Pharmacology, 2000
We investigated how manipulations of the degree of activation of adenosine A 1 and A 2A receptors in¯uences the action of the neuropeptide, calcitonin gene-related peptide (CGRP) on synaptic transmission in hippocampal slices. Field excitatory post-synaptic potentials (EPSPs) from the CA1 area were recorded. 2 When applied alone, CGRP (1 ± 30 nM) was without eect on ®eld EPSPs. However, CGRP (10 ± 30 nM) signi®cantly increased the ®eld EPSP slope when applied to hippocampal slices in the presence of the A 1 receptor antagonist, 1,3-dipropyl-8-cyclopenthyl xanthine (DPCPX, 10 nM), or in the presence of the A 2A adenosine receptor agonist CGS 21680 (10 nM). 3 The A 2A receptor antagonist, ZM 241385 (10 nM) as well as adenosine deaminase (ADA, 2 U ml 71), prevented the enhancement of ®eld EPSP slope caused by CGRP (30 nM) in the presence of DPCPX (10 nM), suggesting that this eect of CGRP requires the concomitant activation of A 2A adenosine receptors by endogenous adenosine. 4 The protein kinase-A inhibitors, N-(2-guanidinoethyl)-5-isoquinolinesulfonamide (HA-1004, 10 mM) and adenosine 3',5'-cyclic monophosphorothioate, Rp-isomer (Rp-cAMPS, 50 mM), as well as the inhibitor of ATP-sensitive potassium (K ATP) channels, glibenclamide (30 mM), prevented the facilitation of synaptic transmission caused by CGRP (30 nM) in the presence of DPCPX (10 nM), suggesting that this eect of CGRP involves both K ATP channels and protein kinase-A. 5 It is concluded that the ability of CGRP to facilitate synaptic transmission in the CA1 area of the hippocampus is under tight control by adenosine, with tonic A 1 receptor activation by endogenous adenosine`braking' the action of CGRP, and the A 2A receptors triggering this action.
Biochimica et Biophysica Acta (BBA) - Biomembranes, 2011
In this paper we review some novel aspects related to the way adenosine A 2A receptors (A 2A R) modulate the action of BDNF or its high-affinity receptors, the TrkB receptors, on synaptic transmission and plasticity, as well as upon cholinergic currents and GABA transporters. Evidence has been accumulating that adenosine A 2A Rs are required for most of the synaptic actions of BDNF. In some cases, where A 2A Rs are constitutively activated (e.g. by endogenous extracellular adenosine), the need for A 2A R activation for the maintenance of the synaptic influences of BDNF can be envisaged from the loss of BDNF effects upon blockade of adenosine A 2A Rs or upon removal of extracellular adenosine with adenosine deaminase. In some other cases, it is necessary to enhance extracellular adenosine levels (e.g. depolarization) or to further activate A 2A Rs (e.g. with selective agonists) to trigger a BDNF neuromodulatory role at the synapses. Age-and cell-dependent differences may determine the above two possibilities, but in all cases it is quite clear that there is close interplay between adenosine A 2A Rs and BDNF TrkB receptors at synapses. The role of lipid rafts in this crosstalk will be discussed. This article is part of a Special Issue entitled: "Adenosine Receptors".
Neuropharmacology, 2014
Brain-derived neurotrophic factor (BDNF) through the activation of its receptor (TrkB-FL) exert welldescribed neuroprotective effects playing a major role in hippocampal synaptic transmission and plasticity such as long-term potentiation (LTP), a molecular surrogate for learning and memory. Impairments in BDNF signalling have been associated to several neurodegenerative disorders such as Alzheimer's disease (AD). Therefore, the reestablishment of BDNF actions is considered a promising strategy for AD treatment. While, most of BDNF synaptic actions, namely on LTP, require the activation of adenosine A 2A receptor (A 2A R), the antagonists of A 2A R have been proven to prevent AD induced deficits in different animal models. Therefore in this work we aimed to evaluate the impact of a chronic in vivo oral administration of an A 2A R antagonist (KW-6002) in the BDNF actions upon hippocampal CA1 LTP. The results showed that chronic blockade of A 2A R in male Wistar rats inhibits the facilitatory action of BDNF upon LTP on hippocampal CA1 area and decreases both mRNA and protein levels of the TrkB-FL receptor in hippocampus. These findings imply that BDNF signalling may be affected in chronic A 2A R blocking conditions.