title: Homeostatic control of synaptic activity by endogenous adenosine is mediated by adenosine kinase.
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.
authors.affiliation: Institute of Pharmacology and Neurosciences, Faculty of Medicine and.
authors.forename: Maria José
authors.initials: MJ
authors.lastname: Diógenes
authors.forename: Raquel
authors.initials: R
authors.lastname: Neves-Tomé
authors.forename: Sergio
authors.initials: S
authors.lastname: Fucile
authors.forename: Katiuscia
authors.initials: K
authors.lastname: Martinello
authors.forename: Maria
authors.initials: M
authors.lastname: Scianni
authors.forename: Panos
authors.initials: P
authors.lastname: Theofilas
authors.forename: Jan
authors.initials: J
authors.lastname: Lopatár
authors.forename: Joaquim A
authors.initials: JA
authors.lastname: Ribeiro
authors.forename: Laura
authors.initials: L
authors.lastname: Maggi
authors.forename: Bruno G
authors.initials: BG
authors.lastname: Frenguelli
authors.forename: Cristina
authors.initials: C
authors.lastname: Limatola
authors.forename: Detlev
authors.initials: D
authors.lastname: Boison
authors.forename: Ana M
authors.initials: AM
authors.lastname: Sebastião
mesh_terms: D000241:Adenosine / Q000502:physiology*; D000248:Adenosine Kinase / Q000235:genetics / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000502:physiology; D056547:CA1 Region, Hippocampal / Q000502:physiology; D056654:CA3 Region, Hippocampal / Q000502:physiology; D055724:Electrophysiological Phenomena / Q000502:physiology; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005110:Extracellular Space / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology*; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019599:Mossy Fibers, Hippocampal / Q000502:physiology; D009473:Neuronal Plasticity / Q000502:physiology; D018408:Patch-Clamp Techniques; D011687:Purines / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000502:physiology; D011963:Receptors, GABA-A / Q000502:physiology; D013569:Synapses / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D011687:Purines; D043705:Receptor, Adenosine A2A; D011963:Receptors, GABA-A; D000248:Adenosine Kinase; D000241:Adenosine