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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.

We previously reported that adenosine, through A2A re- ceptor activation, potentiates synaptic actions of brain-derived neurotro- phic factor (BDNF) in the hippocampus of infant (3-4 weeks) rats. Since A2A-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 A2A receptors in the hip- pocampus 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 exci- tatory postsynaptic potentials recorded from the hippocampus of young adults and aged rats, an action triggered by adenosine A2A receptor acti- vation, since it was blocked by the A2A 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 re- ceptor density shows decreased amounts of TrkB receptors in old adults and aged rats, whereas A2A receptor levels assayed by ligand binding are enhanced in the hippocampus of old adults and aged rats. It is con- cluded that age-related changes in the density of TrkB receptors and of adenosine A2A receptors may be responsible for a nonmonotonous varia- tion of BDNF actions on synaptic transmission in the hippocampus. V C 2007 Wiley-Liss, Inc.