The Journal of Neurophysiology Vol. 78 No. 4 October 1997, pp. 1965-1972
Copyright ©1997 The American Physiological Society

NMDA-Independent LTP by Adenosine A₂ Receptor-Mediated Postsynaptic AMPA Potentiation in Hippocampus

Kofi Kessey¹ and David J. Mogul^{1, 2}

¹ Department of Neurobiology and Physiology and ² Department of Biomedical Engineering, Northwestern University, Evanston, Illinois 60208

Kessey, Kofi and David J. Mogul. NMDA-independent LTP by adenosine A₂ receptor-mediated postsynaptic AMPA potentiation in hippocampus. J. Neurophysiol. 78: 1965-1972, 1997. 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 -amino-3-hydroxy-5-methyl-4-isoxazolepropionic 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-nitroquinoxaline-2,3-dione (20 µM), 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 µM). Blockade of L-type Ca channels with nifedipine (10 µM) 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.

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