| Adenosine acts at A1 receptors (A1Rs) to inhibit transmitter release and hyperpolarize neurons. During synchronized CA3 hippocampal neuronal network activity (bursts), decreasing the postsynaptic calcium influx using antagonists of NMDA receptors and L-type calcium channels resulted in significantly decreased extracellular adenosine levels, producing a paradoxical increase in the probability of spontaneous CA3 bursts. This effect was independent of cannabinoids but was occluded by prior A1R blockade. Voltage clamp recordings revealed that A1Rs modulate the rate of recovery of spontaneous glutamate release following a CA3 burst. A1Rs also mediated a transient decrease of spontaneous glutamate release induced by brief depolarizations of single CA3 pyramidal cells, which could be prevented by buffering calcium in the postsynaptic neuron. These data suggest that postsynaptic calcium entry modulates extracellular adenosine levels, glutamate release, and spontaneous network activity. Adenosine appears to act as a retrograde trans-synaptic neuromodulator at CA3 recurrent collateral synapses.;In addition, transient disruption of A1Rs signaling during spontaneous CA3 bursting induced a significant decrease in the probability of subsequent CA3 bursts. This phenomenon was independent of extracellular adenosine levels or A1Rs activation. Calcium influx through P/Q type calcium channels was required for the induction of this effect. cAMP signaling, restricted to the duration of the transient A1Rs blockade, modulated the amplitude of the subsequent decrease in CA3 burst probability. Voltage clamp recordings of CA3 pyramidal neurons revealed a significant decrease in the probability of glutamate release at recurrent collateral synapses. These data suggest that A1Rs activation during periods of neuronal hyperexcitability acts as a synaptic gain control mechanism and prevents the induction of synaptic homeostasis. |
