The role of
adenosine A2 receptors in normal synaptic transmission and
tetanus-induced long-term potentiation (LTP) was tested by stimulation of the Schaffer collateral pathway and recording of the field excitatory postsynaptic potential (EPSP) in the CA1 region of rat transverse hippocampal slices. Activation of
adenosine A2 receptors with the A2 agonist N6-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)-ethyl]
adenosine (
DPMA; 20 nM) enhanced synaptic transmission during low-frequency test pulses (0. 033 Hz). Paired stimulation before and during
DPMA exposure indicated no paired-pulse facilitation as a result of A2 activation, suggesting that enhancement was not a result of presynaptic modulation.
DPMA enhanced the early phase
alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (
AMPA) component of the EPSP. In contrast,
DPMA had no effect on the N-methyl--
aspartate (
NMDA) component isolated using low extracellular Mg2+ and the
AMPA receptor blocker
6-cyano-7-nitroquinoxaline-2,3-dione (20 microM), indicating that the effects of A2 activation on synaptic transmission were mediated by a postsynaptic enhancement of the
AMPA response. Activation of
adenosine A2 receptors during 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 exposure after prior induction of LTP showed no additional potentiation, indicating that the mechanisms that contribute to both types of increases in synaptic transmission share a common mechanism. A slow onset
NMDA-independent LTP could be induced by application of a
tetanus during perfusion of
DPMA with the
NMDA blocker AP5 (50 microM). Blockade of L-type Ca channels with
nifedipine (10 microM) had no effect on normal synaptic transmission but reduced
NMDA-independent LTP by 32%. Very little
NMDA-independent LTP could be induced after prior saturation of
NMDA-dependent LTP via multiple tetani spaced 10 min apart, indicating that both forms of LTP are eventually convergent on a common mechanism, presumably the postsynaptic
AMPA receptor response. Because extracellular
adenosine levels are modulated by cellular activity throughout the brain and because
adenosine receptor activation can markedly alter levels of synaptic transmission independent of
NMDA receptors,
adenosine may play an important and complex role as a modulator of synaptic transmission in the brain.