Release of Adenosine by Activation of NMDA Receptors in the Hippocampus

Abstract

Adenosine is present in the mammalian brain in large amounts and has potent effects on neuronal activity, but its role in neural signaling is poorly understood. The glutamate receptor agonist N-methyl-D-aspartate (NMDA) caused a presynaptic depression of excitatory synaptic transmission in the CA1 region of guinea pig hippocampal slices. This depression was blocked by an adenosine A1 receptor antagonist, which suggests that activation of the NMDA subtype of glutamate receptor raises the concentration of extracellular adenosine, which acts on presynaptic inhibitory A1 receptors. Strong tetanic stimulation caused a heterosynaptic inhibition that was blocked by both NMDA and A1 receptor antagonists. Enkephalin, which selectively inhibits interneurons, antagonized the heterosynaptic inhibition. These findings suggest that synaptically released glutamate activates NMDA receptors, which in turn releases adenosine, at least in part from interneurons, that acts at a distance to inhibit presynaptically the release of glutamate from excitatory synapses. Thus, interneurons may mediate a widespread purinergic presynaptic inhibition.

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

“…This long-distance A 1 receptor-mediated inhibition operated by endogenous extracellular adenosine also fits beautifully with the idea that adenosine is the main messenger mediating heterosynaptic depression (Manzoni et al, 1994). This consists in the observation that a high frequency stimulation of a particular excitatory pathway causes a depression in nearby pathways (Lynch et al, 1977).…”

“…This consists in the observation that a high frequency stimulation of a particular excitatory pathway causes a depression in nearby pathways (Lynch et al, 1977). When first described, this was proposed to depend on the recruitment on interneurons (Manzoni et al, 1994). This was confirmed in a recent elegant study which established that the high frequency stimulation of a set of Schaffer fibers in hippocampal slices led to the sequential activation of NMDA receptors in GABAergic interneurons and the GABA released would trigger astrocytic activation through GABA B receptors (Kang et al, 1998;Serrano et al, 2006); thanks to the long-range propagation of Ca 2+ waves in astrocytic syncytium (up to 100 mm; reviewed in Halassa et al, 2007;Haydon and Carmignoto, 2006;Scemes and Giaume, 2006), the astrocytes could release ATP in sites facing distant non-stimulated synapses (Pascual et al, 2005;Serrano et al, 2006;Zhang et al, 2003), which, upon extracellular degradation by ecto-nucleotidases, would activate A 1 receptors in these distant non-stimulated synapses (Serrano et al, 2006).…”

The adenosine kinase hypothesis of epileptogenesis

“…This could indeed be an endogenous mechanism to prevent synchronization of neuronal networks. Today it is well recognized that the purine ribonucleoside adenosine is the main messenger mediating heterosynaptic depression (Manzoni et al, 1994).…”

“…In addition to these synaptic effects, A 1 receptors are believed to provide beneficial extra synaptic effects, which are based on a decrease in brain metabolism (Haberg et al, 2000) and the control of astrocyte function (van Calker and Biber, 2005). Tonic activation of A 1 receptors by an endogenous tone of adenosine is believed to lead to long-distance A 1 receptor mediated inhibition and thus to mediate heterosynaptic depression (Manzoni et al, 1994). In regard to epilepsy, A 1 receptors, which have high expression levels in epilepsy-prone regions such as hippocampus (Fredholm et al, 2001), would thus be uniquely positioned to convey paracrine anticonvulsant functions of adenosine (Güttinger et al, 2005a;Güttinger et al, 2005b) and to prevent the spread of epileptogenic activity Kochanek et al, 2006).…”

Integrated Brain Circuits: Neuron-Astrocyte Interaction in Sleep-Related Rhythmogenesis

“…In the hippocampus, high-frequency stimulation of a subset of the Schaffer collateral fibers causes potentiation of the activated synapses (homosynaptic potentiation) and an adenosine-mediated depression of nearby noninnervated synapses (heterosynaptic depression)[111]. Although it has been known that this dynamic process is mediated by adenosine acting through A1 receptors, the cellular source of adenosine had long been undefined.…”