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

Abstract

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.

Adenosine A2A Receptors in the Amygdala Control Synaptic Plasticity and Contextual Fear Memory

“…Thus, different A 2A R antagonists attenuated LTP amplitude in amygdala slices, an effect inexistent upon treatment with shA 2A R as well as in global A 2A R-KO mice; this also testifies that, although we did not directly quantify the reduction of A 2A Rs in the amygdala after shA 2A R treatment, the achieved downregulation of amygdala A 2A Rs with shA 2A R was sufficient to eliminate A 2A R-mediated responses. Notably, A 2A Rs were selectively engaged to control long-term plastic processes and were devoid of effects on the control of basal synaptic transmission or of short-term plasticity, as occurred in hippocampal (Rebola et al, 2008;Costenla et al, 2011) or striatal synapses (d'Alcantara et al, 2001;Flajolet et al, 2008). This impact on synaptic plasticity is in agreement with the enrichment of A 2A Rs in synapses within the amygdala and in particular with the localization of A 2A Rs in glutamatergic synapses, as occurs in other limbic regions such as the hippocampus (Rebola et al, 2005a, b;Costenla et al, 2011).…”

“…Western blot analysis with goat or mouse anti-A 2A R antibodies (1 : 1000; Santa Cruz Biotechnology, Santa Cruz, CA, USA or Millipore, Madrid, Spain, respectively), which selectivity was confirmed by the lack of signal in A 2A Rknockout (KO) mice (Rebola et al, 2005a), or receptor binding analysis with 3 nM of 3 H-SCH58261 (specific activity of 77 Ci/mmol; prepared by GE Healthcare and offered by Dr E Ongini, Schering-Plough, Italy) or 6 nM of 3 H-DPCPX (specific activity of 109.0 Ci/mmol; DuPont NEN, Boston, MA, USA) was carried out in total membranes and membranes from synaptosomes (Costenla et al, 2011;Kaster et al, 2015), whereas the immunocytochemical detection of A 2A Rs in glutamatergic nerve terminals was carried out as described previously (Costenla et al, 2011;Rebola et al, 2005b), using goat anti-A 2A R (1 : 200; Santa Cruz Biotechnology) and guinea-pig anti-vesicular glutamate transporter type 1 (vGluT1; 1 : 1000, Chemicon, Temecula, CA, USA) antibodies.…”

“…Electrophysiological recordings in brain slices were carried out as described previously (Costenla et al, 2011) by extracellularly recording population spikes in the lateral nuclei of the amygdala upon stimulation of the external capsule (EC). Long-term potentiation (LTP) was induced with three pulses of 100 Hz delivered with an interval of 5 s.…”

“…The importance of this modulation system is best heralded by the observation that the overactivation of hippocampal A 2A Rs is necessary and sufficient to trigger spatial memory dysfunction (Li et al, 2015a;Pagnussat et al, 2015). Furthermore, conditions associated with memory deterioration trigger an upregulation of A 2A Rs in the hippocampus leading to abnormal synaptic plasticity (Costenla et al, 2011;Kaster et al, 2015), and A 2A R blockade prevent memory impairment in conditions such as stress, aging, or Alzheimer's disease (eg Batalha et al, 2013;Laurent et al, 2016;Oor et al, 2015;Prediger et al, 2005), an effect mimicked by caffeine (a nonselective adenosine receptor antagonist) both in animal models and in humans (reviewed in Cunha and Agostinho, 2010;Chen, 2014).…”

“…In other brain regions, synaptic plasticity is controlled by the adenosine neuromodulation system (Fredholm et al, 2005), which involves a coordinated action of inhibitory A 1 receptors (A 1 Rs) and facilitatory A 2A receptors (A 2A Rs) to fine tune brain neurotransmission (Cunha, 2008). In hippocampal circuits, A 2A Rs are found in synapses (Rebola et al, 2005a), namely in glutamatergic synapses (Rebola et al, 2005b), and are selectively engaged to control synaptic plasticity (Rebola et al, 2008;Costenla et al, 2011). The importance of this modulation system is best heralded by the observation that the overactivation of hippocampal A 2A Rs is necessary and sufficient to trigger spatial memory dysfunction (Li et al, 2015a;Pagnussat et al, 2015).…”