The role of adenosine A(2) receptors in hippocampal synaptic transmission between the Schaffer collateral pathway and CA1 pyramidal neurons

Adenosine receptor activation can markedly alter levels of synaptic transmission. Reductions in neurotransmission have been reported in response to agonist-mediated adenosine A1 receptor activation. However, the implications of A2 receptor activation on synaptic transmission have not been well explored. The focus of this thesis was to examine the role adenosine A 2 receptors play in the efficacy of excitatory glutamatergic neurotransmission in the Schaffer collateral-CA1 pathway in the rat transverse hippocampal slice.;Activation of adenosine A2 receptors with the A2 agonist DPMA (N6-[2-(3,5-Dimethyoxyphenyl)-2-(2-methylphenyl)-ethyl]adenosine) enhanced normal synaptic transmission by selectively increasing AMPA receptor responses. The A2a receptor agonist, CGS21680, had no effect on synaptic transmission suggesting that the effects of DPMA were through activation of A2b receptors. Both paired stimulation and isolated NMDA receptor responses before and during DPMA exposure showed that enhancement was not a result of presynaptic modulation. The intracellular pathways mediating the effects of A2 receptors were also examined. Inhibition of the cyclic adenosine monophosphate (cAMP)-dependent kinase (PKA) and calcium (Ca 2+) chelation blocked the effect of DPMA, while calcium/calmodulin kinase blockade significantly reduced it.;The level of A2 activation significantly modulated the level of tetanus induced long term potentiation (LTP). This effect was occluded by prior tetanic stimulation. A2 receptor blockade by DMPX and 8-(p-Sulfophenyl)theophylline prevented LTP. Either forskolin or 8-Bromo-cAMP reconstituted LTP during A2 receptor blockade, but not 1,9-dideoxy-forskolin, an inactive forskolin analog.;A slow onset NMDA-independent LTP could be induced by a tetanus during perfusion of DPMA with the NMDA blocker AP5 (50 mum). Blockade of L-type Ca channels with nifedipine (10 muM) had no effect on normal synaptic transmission but reduced NMDA-independent LTP. Very little NMDA-independent LTP could be induced following prior saturation of NMDA-dependent LTP indicating that both forms of LTP are ultimately convergent on a common mechanism, presumably the postsynaptic AMPA receptor response.;The hippocampus plays an important role in forming long term memories. LTP has been proposed as the mechanism that underlies memory formation. This work shows that adenosine A2 receptors can play a significant role in manipulation of neurotransmission in the hippocampus. Because the concentration of extracellular adenosine is greatly increased during neuronal activity, this purine may also play a critical modulatory role in memory formation.