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

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Abstract

Adenosine is a prototypical neuromodulator, which mainly controls excitatory transmission through the activation of widespread inhibitory A1 receptors and synaptically located A2A receptors. It was long thought that the predominant A1 receptor-meditated modulation by endogenous adenosine was a homeostatic process intrinsic to the synapse. New studies indicate that endogenous extracellular adenosine is originated as a consequence of the release of gliotransmitters, namely ATP, which sets a global inhibitory tonus in brain circuits rather than in a single synapse. Thus, this neuron-glia long-range communication can be viewed as a form of non-synaptic transmission (a concept introduced by Professor Sylvester Vizi), designed to reduce noise in a circuit. This neuron-glia-induced adenosine release is also responsible for exacerbating salient information through A1 receptor-mediated heterosynaptic depression, whereby the activation of a particular synapse recruits a neuron-glia network to generate extracellular adenosine that inhibits neighbouring non-tetanised synapses. In parallel, the local activation of facilitatory A2A receptors by adenosine, formed from ATP released only at high frequencies from neuronal vesicles, down-regulates A1 receptors and facilitates plasticity selectively in the tetanised synapse. Thus, upon high-frequency firing of a given pathway, the combined exacerbation of global A1 receptor-mediated inhibition in the circuit (heterosynaptic depression) with the local synaptic activation of A2A receptors in the activated synapse, cooperate to maximise salience between the activated and non-tetanised synapses.

Section snippets

Adenosine in the brain

Adenosine is a prototypic neuromodulator in the nervous system, which means it does not trigger direct neuronal responses but instead fine tunes on-going synaptic transmission. The impact of adenosine modulation is more evident in the control of excitatory rather than inhibitory synapses (reviewed in Dunwiddie and Masino, 2001). The most widely recognised effects of adenosine are operated through inhibitory A1 receptors, one of the most abundant G protein-coupled receptors in brain tissue (

Effects of endogenous adenosine in brain circuits

Apart from the basal ganglia, the experience of the vast majority of researchers exploring adenosine modulation is that adenosine essentially fulfils an inhibitory role mediated by inhibitory A1 receptors (reviewed in Dunwiddie and Masino, 2001). In particular, the seminal work of Tom Dunwiddie has revealed that there is an inhibitory tonus mediated by endogenous adenosine that results from the activation of A1 receptors (Dunwiddie, 1980). This agrees with the general findings that the addition

Source of endogenous extracellular adenosine

The source of endogenous extracellular adenosine during physiological conditions of neuronal firing has been one of the less studied aspects of adenosine neuromodulation. There are two potential metabolic sources able to generate extracellular adenosine: (1) release as such, or (2) extracellular formation from released adenosine nucleotides.

The formation of adenosine from released adenine nucleotides is based on the observation that most cell types in the brain can release ATP (reviewed in

Adenosine as a hetero-synaptic modulator—A1 receptors

Several groups noted that the blockade of ecto-nucleotidases decreases the extracellular levels of endogenous adenosine in brain slices (Pascual et al., 2005, Martin et al., 2007, Serrano et al., 2006). In particular, the innovative methodology devised by Nicholas Dale to quantify on-line the extracellular levels of ATP and adenosine (Llaudet et al., 2005, Pearson et al., 2001) confirmed that the extracellular catabolism of ATP contributed for the basal extracellular levels of adenosine in

Adenosine as a synaptic modulator—A2A receptors

This ‘paracrine’-like role of adenosine acting broadly in large groups of synapses in a non-synaptic (Vizi, 1984) or volume transmission-like manner (Agnati et al., 1986) should not underscore a complementary role fulfilled by adenosine as an ‘autocrine’-like signalling molecule restricted to a particular synapse. In fact, there is ground to propose that the role of adenosine in the control of synaptic plasticity might not only be limited to the ‘paracrine’-like action of inhibitory A1

An integrated view of adenosine modulation

Overall, the ‘paracrine’-like role of A1 receptor-mediated inhibition and the ‘autocrine’-like facilitatory role of A2A receptors work in tandem to guarantee a maximal salience between stimulated and non-tetanised synapses (Fig. 1). At low frequencies of nerve stimulation (used in the majority of studies), it is only possible to highlight a role of A1 receptors, which impose a global tonic inhibition of excitatory transmission designed to decrease noise (Fig. 1, upper panel). Facilitatory A2A

Acknowledgments

Due to space limitations, I mostly quoted reviews rather original papers, thus leaving unquoted several colleagues, to whom I apologise. I thank the continuous support of Fundação para a Ciência e a Tecnologia and the continuous discussions with the lab members and different colleagues over the years.

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