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 A(1) (A(1)R) and facilitatory A(2A) receptors (A(2A)R). Both A(1)R and A(2A)R modulate hippocampal glutamate release and NMDA-dependent long-term potentiation (LTP) but ageing affects the density of both A(1)R and A(2A)R. We tested the effects of selective A(1)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 A(1)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.