Homeostatic control of synaptic activity by endogenous adenosine is mediated by adenosine kinase

Maria José Diógenes, Raquel Neves-Tomé, Sergio Fucile, Katiuscia Martinello, Maria Scianni, Panos Theofilas, Jan Lopatář, Joaquim A. Ribeiro, Laura Maggi, Bruno G. Frenguelli, Cristina Limatola, Detlev Boison, Ana M. Sebastião

Research output: Contribution to journalArticlepeer-review

Abstract

Extracellular adenosine, a key regulator of neuronal excitability, is metabolized by astrocyte-based enzyme adenosine kinase (ADK). We hypothesized that ADK might be an upstream regulator of adenosine-based homeostatic brain functions by simultaneously affecting several downstream pathways. We therefore studied the relationship between ADK expression, levels of extracellular adenosine, synaptic transmission, intrinsic excitability, and brain-derived neurotrophic factor (BDNF)-dependent synaptic actions in transgenic mice underexpressing or overexpressing ADK. We demonstrate that ADK: 1) Critically influences the basal tone of adenosine, evaluated by microelectrode adenosine biosensors, and its release following stimulation; 2) determines the degree of tonic adenosine-dependent synaptic inhibition, which correlates with differential plasticity at hippocampal synapses with low release probability; 3) modulates the age-dependent effects of BDNF on hippocampal synaptic transmission, an action dependent upon co-activation of adenosine A2A receptors; and 4) influences GABAA receptor-mediated currents in CA3 pyramidal neurons. We conclude that ADK provides important upstream regulation of adenosine-based homeostatic function of the brain and that this mechanism is necessary and permissive to synaptic actions of adenosine acting on multiple pathways. These mechanistic studies support previous therapeutic studies and implicate ADK as a promising therapeutic target for upstream control of multiple neuronal signaling pathways crucial for a variety of neurological disorders.

Original languageEnglish
Pages (from-to)67-80
Number of pages14
JournalCerebral Cortex
Volume24
Issue number1
DOIs
Publication statusPublished - Jan 2014

Keywords

  • Adenosine
  • Brain-derived neurotrophic factor
  • GABA
  • Homeostasis
  • Transgenic mice

ASJC Scopus subject areas

  • Cognitive Neuroscience
  • Cellular and Molecular Neuroscience

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