Adenosine A2A receptors facilitate synaptic NMDA currents in CA1 pyramidal neurons

Background and Purpose Experimental Approach NMDA receptors play a key role in both synaptic plasticity and neurodegeneration. Adenosine is an endogenous neuromodulator and through membrane receptors of the A(2A) subtype can influence both synaptic plasticity and neuronal death. The present work was designed to evaluate the influence of adenosine A(2A) receptors upon NMDA receptor activity in CA1 hippocampal neurons. We discriminated between modulation of synaptic versus extrasynaptic receptors, since extrasynaptic NMDA receptors are mostly associated with neurodegeneration while synaptic NMDA receptors are linked to plasticity phenomena. Whole-cell patch-clamp recordings were obtained to evaluate NMDA receptor actions on CA1 pyramidal neurons of young adult (5-10 weeks) male Wistar rat hippocampus. Key Results Conclusion and Implications Activation of A(2A) receptors with CGS 21680 (30 nM) consistently facilitated chemically-evoked NMDA receptor-currents (NMDA-PSCs) and afferent-evoked NMDA-currents (NMDA-EPSCs), an action prevented by an A(2A) receptor antagonist (SCH58261, 100 nM) and a PKA inhibitor, H-89 (1 mu M). These actions did not reflect facilitation in glutamate release since there was no change in NMDA-EPSCs paired pulse ratio. A(2A) receptor actions were lost in the presence of an open-channel NMDA receptor blocker, MK-801 (10 mu M), but persisted in the presence of memantine, at a concentration (10 mu M) known to preferentially block extrasynaptic NMDA receptors. These results show that A(2A) receptors exert a positive postsynaptic modulatory effect over synaptic, but not extrasynaptic, NMDA receptors in CA1 neurons and, therefore, under non-pathological conditions may contribute to shift the dual role of NMDA receptors towards enhancement of synaptic plasticity.