NMDA-INDEPENDENT LTP BY ADENOSINE A(2) RECEPTOR-MEDIATED POSTSYNAPTICAMPA POTENTIATION IN HIPPOCAMPUS

The role of adenosine A(2) receptors in normal synaptic transmission a nd tetanus-induced long-term potentiation (LTP) was tested by stimulat ion of the Schaffer collateral pathway and recording of the field exci tatory postsynaptic potential (EPSP) in the CA1 region of rat transver se hippocampal slices. Activation of adenosine A(2) receptors with the A(2) agonist imethoxyphenyl)-2-(2-methylphenyl)-ethyl]adenosine (DPMA ; 20 nM) enhanced synaptic transmission during low-frequency test puls es (0.033 Hz). Paired stimulation before and during DPMA exposure indi cated no paired-pulse facilitation as a result of A(2)-activation, sug gesting that enhancement was not a result of presynaptic modulation. D PMA enhanced the early phase lpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) component of the EPSP. In contrast, DPMA had no effect on the N-methyl-D-aspartate (NMDA) component isolated using low extracellular Mg2+ and the AMPA receptor blocker 6-cyano-7-nitroquino xaline-2,3-dione (20 mu M), indicating that the effects of A(2) activa tion on synaptic transmission were mediated by a postsynaptic enhancem ent of the AMPA response. Activation of adenosine A(2) receptors durin g a brief tetanus (100 Hz, 1 s) increased the level of LTP by 36% over that seen in response to a tetanus under control conditions. DPMA exp osure after prior induction of LTP showed no additional potentiation, indicating that the mechanisms that contribute to both types of increa ses in synaptic transmission share a common mechanism. A slow onset NM DA-independent LTP could be induced by application of a tetanus during perfusion of DPMA with the NMDA blocker APS (50 mu M). Blockade of L- type Ca channels with nifedipine (10 mu M) had no effect on normal syn aptic transmission but reduced NMDA-independent LTP by 32%. Very littl e NMDA-independent LTP could be induced after prior saturation of NMDA -dependent LTP via multiple tetani spaced 10 min apart, indicating tha t both forms of LTP are eventually convergent on a common mechanism, p resumably the postsynaptic AMPA receptor response. Because extracellul ar adenosine levels are modulated by cellular activity throughout the brain and because adenosine receptor activation can markedly alter lev els of synaptic transmission independent of NMDA receptors, adenosine may play an important and complex role as a modulator of synaptic tran smission in the brain.