Activity-dependent release of endogenous adenosine modulates synaptic responses in the rat hippocampus

Abstract

Adenosine is a potent inhibitory modulator of synaptic transmission in the CNS, but its role in normal physiological function is unclear. In the present experiments, we have found electrophysiological evidence for activity-dependent release of adenosine from hippocampal slices evoked by physiologically relevant stimulation, and have demonstrated that this adenosine modifies synaptic activity in this brain region. When two independent excitatory pathways to the CA1 pyramidal neurons are used to evoke field EPSP responses, prior activation of one pathway will inhibit the EPSP evoked via the other input. This inhibition can be antagonized by the nonselective adenosine receptor antagonist theophylline, and by the selective A1 receptor antagonist 8-cyclopentyltheophylline, suggesting that the inhibitory response is due to the release of endogenous adenosine that activates presynaptic release-modulating A1 receptors. This inhibition can be observed following a single stimulus to the conditioning pathway, although it is more pronounced when a train of conditioning pulses is used, and is maximal following a train of 16-32 stimuli (at 100 Hz). When a train of four conditioning pulses is used, the inhibition appears with a latency of approximately 50 msec, peaks approximately 200-250 msec following the conditioning train, and recovers to baseline between 1 and 2 sec. Further evidence that this inhibition of excitatory transmission is mediated via adenosine is provided by the observation that superfusion with dipyridamole (an adenosine uptake inhibitor), and the adenosine deaminase inhibitor erythro-(2-hydroxy-3-nonyl)adenine, enhanced both the duration and amplitude of the inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)

Activity-Dependent Release of Adenosine Contributes to Short-Term Depression at CA3-CA1 Synapses in Rat Hippocampus

“…Adenosine can be released via facilitated transport from hippocampal pyramidal cells (Brundege and Dunwiddie 1996;Jonzon and Fredholm 1985) and/or glial cells (Caciagli et al 1988). An antagonist of adenosine transport did not reduce homosynaptic depression in our experiments, however, consistent with earlier studies of hippocampal heterosynaptic depression (Mitchell et al 1993). Although our evidence is indirect and derived by excluding alternative hypotheses, taken with previous demonstrations of Ca 2ϩ -dependent adenosine release (e.g., Manzoni et al 1994;Pull and McIlwain 1973), we suggest that high-frequency stimulation causes the exocytosis of adenosine-containing vesicles, possibly as a co-transmitter.…”

“…Tetanic stimulation causes release of two modulators of glutamatergic synaptic transmission, adenosine and adenine nucleotides (e.g., McIlwain 1972;Mitchell et al 1993;Wieraszko et al 1989). Activation of A 1 receptors with exogenous adenosine depresses excitatory synaptic transmission and activates a postsynaptic K ϩ conductance in hippocampus (e.g., Greene and Haas 1991;Thompson et al 1992Thompson et al , 1993Wu and Saggau 1997).…”

“…At the frog neuromuscular junction, activation of presynaptic adenosine receptors, as the result of adenine nucleotide release and subsequent conversion to adenosine, underlies short-term homosynaptic depression at low stimulation frequencies (Redman and Silinsky 1994). At hippocampal Schaffer collateral-CA1 cell synapses, adenosine mediates heterosynaptic depression induced with 100-Hz stimulation for 0.3-1 s (Manzoni et al 1994;Mitchell et al 1993). There are several potential sources of endogenous adenosine, including glia (Caciagli et al 1988), interneurons (Manzoni et al 1994), and pyramidal cells (Brundege and Dunwiddie 1996).…”

Adenosine induces hemeoxygenase‐1 expression in microglia through the activation of phosphatidylinositol 3‐kinase and nuclear factor E2‐related factor 2

“…Under pathological conditions, such as ischemia, stroke and seizure, the extracellular adenosine concentration is increased by 30-100 times that in the normal brain. Glia and neurons release adenosine and adenine nucleotides that may be converted into adenosine into the extracellular space (Cunha et al, 1996;Cunha, 2001;Mitchell et al, 1993;Parkinson and Xiong, 2004;Parkinson et al, 2005;von Lubitz, 1999). Therefore, adenosine could exert expanded neuroprotective effect in injured brain.…”

Different cellular sources and different roles of adenosine: A1 receptor-mediated inhibition through astrocytic-driven volume transmission and synapse-restricted A2A receptor-mediated facilitation of plasticity

“…Thus, adenosine would be locally generated in the synapse in amounts directly proportional to synaptic activity, and would act through inhibitory A 1 receptors as a feedback mechanism to restraint excessive synaptic activation . Two parallel mechanisms were considered to understand how the levels of synaptic adenosine would parallel synaptic activity: (1) adenosine would be formed extracellularly upon catabolism of released ATP originated from synaptic vesicles (reviewed in Sperlágh and Vizi, 1996); (2) adenosine would be released from the postsynaptic neuron as a consequence of the activation of ionotropic glutamate receptors (see Dunwiddie and Diao, 1994;Mitchell et al, 1993a). Irrespective of the source of synaptic adenosine, the predominance of A 1 receptor-mediated inhibition behaved as a homeostatic 'autocrine'-like role restricted to a particular excitatory synapse.…”