Astrocytic adenosine kinase regulates basal synaptic adenosine levels and seizure activity but not activity-dependent adenosine release in the hippocampus

Lori-An V. Etherington, Graham E. Patterson, Louise Meechan, Detlev Boison, Andrew J. Irving, Nicholas Dale, Bruno G. Frenguelli

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    Adenosine is an endogenous inhibitor of excitatory synaptic transmission with potent anticonvulsant properties in the mammalian brain. Given adenosine's important role in modulating synaptic transmission, several mechanisms exist to regulate its extracellular availability. One of these is the intracellular enzyme adenosine kinase (ADK), which phosphorylates adenosine to AMP. We have investigated the role that ADK plays in regulating the presence and effects of extracellular adenosine in area CA1 of rat hippocampal slices. Inhibition of ADK activity with 5'-iodotubercidin (IODO; 5 mu M) raised extracellular adenosine, as measured with adenosine biosensors, and potently inhibited field excitatory post-synaptic 2 potentials (fEPSPs) in an adenosine A(1)R-dependent manner. In nominally Mg2+-free aCSF, which facilitated the induction of electrically-evoked epileptiform activity, adenosine biosensor recordings revealed that seizures were accompanied by the transient release of adenosine. Under these conditions, IODO also inhibited the fEPSP and greatly suppressed epileptiform activity evoked by brief, high-frequency stimulation. During spontaneous seizures evoked by the AIR antagonist CPT, adenosine release was unaffected by IODO. This suggests that ADK activity does not limit activity-dependent adenosine release. On the basis of strong ADK immunoreactivity in GFAP-positive cells, astrocytes are likely to play a key role in regulating basal adenosine levels. It is this action of ADK on the basal adenosine tone that is permissive to seizure activity, and, by extension, other forms of activity-dependent neuronal activity such as synaptic plasticity. (c) 2008 Elsevier Ltd. All rights reserved.

    Original languageEnglish
    Pages (from-to)429-437
    Number of pages9
    Issue number2
    Publication statusPublished - Feb 2009


    • Adenosine kinase
    • Seizure
    • Adenosine
    • Epilepsy
    • Iodotubercidin
    • Astrocytes
    • CA1 REGION
    • SLICES
    • BRAIN

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