Publications (6)26.4 Total impact
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Article: Impaired TrkB receptor signaling contributes to memory impairment in APP/PS1 mice.
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ABSTRACT: Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal plasticity, learning, and memory. Levels of BDNF and its main receptor TrkB (TrkB.TK) have been reported to be decreased while the levels of the truncated TrkB (TrkB.T1) are increased in Alzheimer's disease. We show here that incubation with amyloid-β increased TrkB.T1 receptor levels and decreased TrkB.TK levels in primary neurons. In vivo, APPswe/PS1dE9 transgenic mice (APdE9) showed an age-dependent relative increase in cortical but not hippocampal TrkB.T1 receptor levels compared with TrkB.TK. To investigate the role of TrkB isoforms in Alzheimer's disease, we crossed AP mice with mice overexpressing the truncated TrkB.T1 receptor (T1) or the full-length TrkB.TK isoform. Overexpression of TrkB.T1 in APdE9 mice exacerbated their spatial memory impairment while the overexpression of TrkB.TK alleviated it. These data suggest that amyloid-β changes the ratio between TrkB isoforms in favor of the dominant-negative TrkB.T1 isoform both in vitro and in vivo and supports the role of BDNF signaling through TrkB in the pathophysiology and cognitive deficits of Alzheimer's disease.Neurobiology of aging 12/2011; 33(6):1122.e23-39. · 5.94 Impact Factor -
Article: Enhanced role of adenosine A(2A) receptors in the modulation of LTP in the rat hippocampus upon ageing.
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ABSTRACT: Adenosine neuromodulation depends on a balanced activation of inhibitory A₁ (A₁R) and facilitatory A(₂A) receptors (A(₂A) R). Both A₁ R and A(₂A) R modulate hippocampal glutamate release and NMDA-dependent long-term potentiation (LTP) but ageing affects the density of both A₁ R and A(₂A) R. We tested the effects of selective A₁ R and A(2A) R 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 A(₂A) R 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 A₁ R 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 A(₂A) R mRNA in the hippocampus and a higher number of glutamatergic nerve terminals equipped with A(2A) R in aged (67 ± 6%) compared with middle-aged (34 ± 7%) and young rats (25 ± 5%). The results show an enhanced A(₂A) R-mediated modulation of LTP in aged rats, in accordance with the age-associated increased expression and density of A(₂A) R in glutamatergic terminals. This age-associated gain of function of A(₂A) R modulating synaptic plasticity may underlie the ability of A(₂A) R antagonists to prevent memory dysfunction in aged animals.European Journal of Neuroscience 05/2011; 34(1):12-21. · 3.63 Impact Factor -
Article: Modulation of brain-derived neurotrophic factor (BDNF) actions in the nervous system by adenosine A(2A) receptors and the role of lipid rafts.
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ABSTRACT: 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 cross-talk will be discussed. This article is part of a Special Issue entitled: "Adenosine Receptors".Biochimica et Biophysica Acta 05/2011; 1808(5):1340-9. · 4.66 Impact Factor -
Article: Enhancement of LTP in aged rats is dependent on endogenous BDNF.
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ABSTRACT: 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 A(2A) receptors (A(2A)R), 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 A(2A)R 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.Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 04/2011; 36(9):1823-36. · 6.99 Impact Factor -
Article: Influence of age on BDNF modulation of hippocampal synaptic transmission: interplay with adenosine A2A receptors.
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ABSTRACT: We previously reported that adenosine, through A(2A) receptor activation, potentiates synaptic actions of brain-derived neurotrophic factor (BDNF) in the hippocampus of infant (3-4 weeks) rats. Since A(2A)-receptor-mediated actions are more evident in old than in young rats and since the therapeutic potential for BDNF-based strategies is greater in old subjects, we now evaluated synaptic actions of BDNF and the levels of TrkB receptors and of adenosine A(2A) receptors in the hippocampus of three groups of adult rats: young adults (10-16 weeks), old adults (36-38 weeks), and aged (70-80 weeks), as well as in one group of infant (3-4 weeks) rats. BDNF (20 ng/ml) enhances field excitatory postsynaptic potentials recorded from the hippocampus of young adults and aged rats, an action triggered by adenosine A(2A) receptor activation, since it was blocked by the A(2A) receptor antagonist, ZM 241385. In the other groups of animals BDNF (20 ng/ml) was virtually devoid of action on synaptic transmission. Western blot analysis of receptor density shows decreased amounts of TrkB receptors in old adults and aged rats, whereas A(2A) receptor levels assayed by ligand binding are enhanced in the hippocampus of old adults and aged rats. It is concluded that age-related changes in the density of TrkB receptors and of adenosine A(2A) receptors may be responsible for a nonmonotonous variation of BDNF actions on synaptic transmission in the hippocampus.Hippocampus 02/2007; 17(7):577-85. · 5.18 Impact Factor -
Article: Modulation of brain-derived neurotrophic factor (BDNF) actions in the nervous system by adenosine A2A receptors and the role of lipid rafts
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ABSTRACT: In this paper we review some novel aspects related to the way adenosine A2A receptors (A2AR) 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 A2ARs are required for most of the synaptic actions of BDNF. In some cases, where A2ARs are constitutively activated (e.g. by endogenous extracellular adenosine), the need for A2AR activation for the maintenance of the synaptic influences of BDNF can be envisaged from the loss of BDNF effects upon blockade of adenosine A2ARs 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 A2ARs (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 A2ARs and BDNF TrkB receptors at synapses. The role of lipid rafts in this cross-talk will be discussed. This article is part of a Special Issue entitled: “Adenosine Receptors”.Biochimica et Biophysica Acta (BBA) - Biomembranes.
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Institutions
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2007–2011
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University of Lisbon
- Faculdade de Medicina
Lisbon, Lisbon, Portugal
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