Enhanced role of adenosine A2A receptors in the modulation of LTP in the rat hippocampus upon ageing

Adenosine neuromodulation depends on a balanced activation of inhibitory A1 (A1R) and facilitatory A2A receptors (A2AR). Both A1R and A2AR modulate hippocampal glutamate release and NMDA-dependent long-term potentiation (LTP) but ageing affects the density of both A1R and A2AR. We tested the effects of selective A1R and A2AR antagonists in the modulation of synaptic transmission and plasticity in rat hippocampal slices from three age groups (young adults, 2–3 month; middle-aged adults, 6–8 months; aged, 18–20 months). The selective A2AR antagonist SCH58261 (50 nm) attenuated LTP in all age groups, with a larger effect in aged ()63 ± 7%) than in middle-aged adults ()36 ± 9%) or young adult rats ()36 ± 9%). In contrast, the selective A1R antagonist DPCPX (50 nm) increased LTP magnitude in young adult rats (+42 ± 6%), but failed to affect LTP magnitude in the other age groups. Finally, in the continuous presence of DPCPX, SCH58261 caused a significantly larger inhibition of LTP amplitude in aged ()71 ± 45%) than middle-aged ()28 ± 9%) or young rats ()11 ± 2%). Accordingly, aged rats displayed an increased expression of A2AR mRNA in the hippocampus and a higher number of glutamatergic nerve terminals equipped with A2AR in aged (67 ± 6%) compared with middle-aged (34 ± 7%) and young rats (25 ± 5%). The results show an enhanced A2AR-mediated modulation of LTP in aged rats, in accordance with the age-associated increased expression and density of A2AR in glutamatergic terminals. This age-associated gain of function of A2AR modulating synaptic plasticity may underlie the ability of A2AR antagonists to prevent memory dysfunction in aged animals

Enhancement of LTP in aged rats is dependent on endogenous BDNF

© 2011 American College of Neuropsychopharmacology.Long-term potentiation (LTP), considered the neurophysiological basis for learning and memory, is facilitated by brain-derived neurotrophic factor (BDNF), an action more evident when LTP is evoked by weak θ-burst stimuli and dependent on co-activation of adenosine A2A receptors (A2AR), which are more expressed in aged rats. As θ-burst stimuli also favor LTP in aged animals, we hypothesized that enhanced LTP in aging could be related to changes in neuromodulation by BDNF. The magnitude of CA1 LTP induced by a weak θ-burst stimuli delivered to the Schaffer collaterals was significantly higher in hippocampal slices taken from 36 to 38 and from 70 to 80-week-old rats, when compared with LTP magnitude in slices from 4 or 10 to 15-week-old rats; this enhancement does not impact in cognitive improvement as aged rats revealed an impairment on hippocampal-dependent learning and memory performance, as assessed by the Morris water maze tests. The scavenger for BDNF, TrkB-Fc, and the inhibitor of Trk phosphorylation, K252a, attenuated LTP in slices from 70 to 80-week-old rats, but not from 10 to 15-week-old rats. When exogenously added, BDNF significantly increased LTP in slices from 4 and 10 to 15-week-old rats, but did not further increased LTP in 36 to 38 or 70 to 80-week-old rats. The effects of exogenous BDNF on LTP were prevented by the A2AR antagonist, SCH58261 (7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine). These results indicate that the higher LTP magnitude observed upon aging, which does not translate into improved spatial memory performance, is a consequence of an increase in the tonic action of endogenous BDNF.Fundação para a Ciência e Tecnologia, Fundação Calouste Gulbenkian and EU (COST B-30 concerted action

Adenosine A2AReceptors Regulate the Extracellular Accumulation of Excitatory Amino Acids upon Metabolic Dysfunction in Chick Cultured Retinal Cells

The role of endogenous extracellular adenosine as a tonic modulator of the extracellular accumulation of excitatory amino acids (glutamate and aspartate) caused by metabolic inhibition was investigated in cultured retinal cells. The selective adenosine A2Areceptor antagonist, 4-[2-[7-amino-2-(2-furyl)(1,2,4)-triazin-5-ylamino]-ethyl]phenol (ZM241385) (50 n ), increased the release of glutamate (three- to four-fold) and of aspartate (nearly two-fold) upon iodoacetic acid-induced glycolysis inhibition, in the presence or in the absence of Ca2+. Blockade of tonic activation of A2Areceptors by ZM241385 also increased (nearly two-fold) the ischemia-induced release of glutamate and aspartate. Furthermore, another selective A2Areceptor antagonist, 5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo[4,3- e ]-1,2,4-triazolo[1,5- c ]pyrimidine (SCH58261), also increased the release of aspartate and glutamate by about two-fold in cells submitted to glycolysis inhibition. In contrast, the selective adenosine A1receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) (100 n ), did not significantly modify the extracellular accumulation of either glutamate or aspartate caused by inducers of chemical ischemia or glycolytic inhibitors. Inhibition of glycolysis also increased (about three-fold) the extracellular accumulation of GABA, which was virtually unchanged by ZM241385. Furthermore, the GABAAreceptor antagonist, bicuculline (10 [mu]), only increased (nearly two-fold) the iodoacetic acid-induced Ca2+-dependent release of glutamate, whereas the GABABreceptor antagonist, 3-aminopropyl(diethoxymethyl) phosphinic acid, CGP35348 (100 [mu]), was devoid of effects on the extracellular accumulation of glutamate and aspartate. These results show that endogenous extracellular adenosine, which rises under conditions of inhibited glycolysis, tonically inhibits the extracellular accumulation of excitatory amino acid through the activation of A2A, but not A1, adenosine receptors, and this effect is independent of GABAAand GABABfunctions in the cultured retinal cells.http://www.sciencedirect.com/science/article/B6WFD-45F4J3T-39/1/d76e568b0a8d49a393eeeb30f961101

Caffeine reverts memory but not mood impairment in a depression-prone mouse strain with up-regulated Adenosine A(2A) receptor in hippocampal glutamate synapses

Caffeine prophylactically prevents mood and memory impairments through adenosine A(2A) receptor (A(2A)R) antagonism. A(2A)R antagonists also therapeutically revert mood and memory impairments, but it is not known if caffeine is also therapeutically or only prophylactically effective. Since depression is accompanied by mood and memory alterations, we now explored if chronic (4 weeks) caffeine consumption (0.3 g/L) reverts mood and memory impairment in helpless mice (HM, 12 weeks old), a bred-based model of depression. HM displayed higher immobility in the tail suspension and forced swimming tests, greater anxiety in the elevated plus maze, and poorer memory performance (modified Y-maze and object recognition). HM also had reduced density of synaptic (synaptophysin, SNAP-25), namely, glutamatergic (vGluT1; -22 +/- 7 %) and GABAergic (vGAT; -23 +/- 8 %) markers in the hippocampus. HM displayed higher A(2A)R density (72 +/- 6 %) in hippocampal synapses, an enhanced facilitation of hippocampal glutamate release by the A(2A)R agonist, CGS21680 (30 nM), and a larger LTP amplitude (54 +/- 8 % vs. 21 +/- 5 % in controls) that was restored to control levels (30 +/- 10 %) by the A(2A)R antagonist, SCH58261 (50 nM). Notably, caffeine intake reverted memory deficits and reverted the loss of hippocampal synaptic markers but did not affect helpless or anxiety behavior. These results reinforce the validity of HM as an animal model of depression by showing that they also display reference memory deficits. Furthermore, caffeine intake selectively reverted memory but not mood deficits displayed by HM, which are associated with an increased density and functional impact of hippocampal A(2A)R controlling synaptic glutamatergic function.NARSADDARPA [09-68-ESR-FP-010]Fundacao para a Ciencia e para a Tecnologia [PTDC/SAU-NEU/122254/2010, PEst-C/SAU/LA0001/2013-2014]QREN [CENTRO-07-ST24-FEDER-002006]program Egide-PessoaCAPES FCT (Ciencia sem Fronteiras