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 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.