%0 Journal Article %T Homeostatic control of synaptic activity by endogenous adenosine is mediated by adenosine kinase. %+ Faculty of Medicine %+ Unit of Neurosciences %+ Department of Physiology and Pharmacology %+ Istituto Neurologico Mediterraneo (NEUROMED I.R.C.C.S.) %+ R.S. Dow Neurobiology Laboratories %+ School of Life Sciences %+ Neuroscience Programme %A Diógenes, Maria José %A Neves-Tomé, Raquel %A Fucile, Sergio %A Martinello, Katiuscia %A Scianni, Maria %A Theofilas, Panos %A Lopatár, Jan %A Ribeiro, Joaquim A %A Maggi, Laura %A Frenguelli, Bruno G %A Limatola, Cristina %A Boison, Detlev %A Sebastião, Ana M %Z The work done in Portugal was supported by Fundação para a Ciência e Tecnologia (FCT) and EU (COST B-30) concerted action. Work from the UK was supported by an Epilepsy Research UK PhD studentship to J.L. Work performed in the USA was supported by NIH grants R01-NS061844 and R01 NS065957. Work in Italy was supported by the Ministero della Salute, PRIN 2009. %< avec comité de lecture %@ 1047-3211 %J Cerebral Cortex %I Oxford University Press (OUP) %V 24 %N 1 %P 67-80 %8 2014-01 %D 2014 %R 10.1093/cercor/bhs284 %M 22997174 %K adenosine %K brain-derived neurotrophic factor %K GABA %K homeostasis %K transgenic mice %Z Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/NeurobiologyJournal articles %X 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. %G English %2 https://riip.hal.science/pasteur-00961607/document %2 https://riip.hal.science/pasteur-00961607/file/Diogeneetal2012.pdf %L pasteur-00961607 %U https://riip.hal.science/pasteur-00961607 %~ RIIP %~ RIIP_FCB