title: Adenosine Kinase Deficiency in the Brain Results in Maladaptive Synaptic Plasticity.
abstract: Adenosine kinase (ADK) deficiency in human patients (OMIM:614300) disrupts the methionine cycle and triggers hypermethioninemia, hepatic encephalopathy, cognitive impairment, and seizures. To identify whether this neurological phenotype is intrinsically based on ADK deficiency in the brain or if it is secondary to liver dysfunction, we generated a mouse model with a brain-wide deletion of ADK by introducing a Nestin-Cre transgene into a line of conditional ADK deficient Adkfl/flmice. These AdkΔbrainmice developed a progressive stress-induced seizure phenotype associated with spontaneous convulsive seizures and profound deficits in hippocampus-dependent learning and memory. Pharmacological, biochemical, and electrophysiological studies suggest enhanced adenosine levels around synapses resulting in an enhanced adenosine A1receptor (A1R)-dependent protective tone despite lower expression levels of the receptor. Theta-burst-induced LTP was enhanced in the mutants and this was dependent on adenosine A2Areceptor (A2AR) and tropomyosin-related kinase B signaling, suggesting increased activation of these receptors in synaptic plasticity phenomena. Accordingly, reducing adenosine A2Areceptor activity in AdkΔbrainmice restored normal associative learning and contextual memory and attenuated seizure risk. We conclude that ADK deficiency in the brain triggers neuronal adaptation processes that lead to dysregulated synaptic plasticity, cognitive deficits, and increased seizure risk. Therefore, ADK mutations have an intrinsic effect on brain physiology and may present a genetic risk factor for the development of seizures and learning impairments. Furthermore, our data show that blocking A2AR activity therapeutically can attenuate neurological symptoms in ADK deficiency.
  
  
  
  A novel human genetic condition (OMIM #614300) that is based on mutations in the adenosine kinase (Adk) gene has been discovered recently. Affected patients develop hepatic encephalopathy, seizures, and severe cognitive impairment. To model and understand the neurological phenotype of the human mutation, we generated a new conditional knock-out mouse with a brain-specific deletion of Adk (AdkΔbrain). Similar to ADK-deficient patients, AdkΔbrainmice develop seizures and cognitive deficits. We identified increased basal synaptic transmission and enhanced adenosine A2Areceptor (A2AR)-dependent synaptic plasticity as the underlying mechanisms that govern these phenotypes. Our data show that neurological phenotypes in ADK-deficient patients are intrinsic to ADK deficiency in the brain and that blocking A2AR activity therapeutically can attenuate neurological symptoms in ADK deficiency.
authors.affiliation: R.S. Dow Neurobiology Laboratories and.
authors.forename: Ursula S
authors.identifier: 0000-0002-3646-7089
authors.initials: US
authors.lastname: Sandau
authors.affiliation: Institute of Pharmacology and Neurosciences, Faculty of Medicine, Unit of Neurosciences, and.|Instituto de Medicina Molecular, Faculty of Medicine, University of Lisbon, 1649-028 Lisbon, Portugal, and.
authors.forename: Mariana
authors.initials: M
authors.lastname: Colino-Oliveira
authors.affiliation: R.S. Dow Neurobiology Laboratories and.
authors.forename: Abbie
authors.identifier: 0000-0003-2154-8393
authors.initials: A
authors.lastname: Jones
authors.affiliation: R.S. Dow Neurobiology Laboratories and.
authors.forename: Bounmy
authors.identifier: 0000-0002-2741-2019
authors.initials: B
authors.lastname: Saleumvong
authors.affiliation: R.S. Dow Neurobiology Laboratories and.
authors.forename: Shayla Q
authors.initials: SQ
authors.lastname: Coffman
authors.affiliation: Department of Comparative Medicine, Legacy Research Institute, Portland, Oregon 97232.
authors.forename: Long
authors.identifier: 0000-0002-4474-6491
authors.initials: L
authors.lastname: Liu
authors.affiliation: Institute of Pharmacology and Neurosciences, Faculty of Medicine, Unit of Neurosciences, and.|Instituto de Medicina Molecular, Faculty of Medicine, University of Lisbon, 1649-028 Lisbon, Portugal, and.
authors.forename: Catarina
authors.identifier: 0000-0002-9633-7999
authors.initials: C
authors.lastname: Miranda-Lourenço
authors.affiliation: Institute of Pharmacology and Neurosciences, Faculty of Medicine, Unit of Neurosciences, and.|Instituto de Medicina Molecular, Faculty of Medicine, University of Lisbon, 1649-028 Lisbon, Portugal, and.
authors.forename: Cátia
authors.initials: C
authors.lastname: Palminha
authors.affiliation: Instituto de Medicina Molecular, Faculty of Medicine, University of Lisbon, 1649-028 Lisbon, Portugal, and.
authors.forename: Vânia L
authors.identifier: 0000-0001-6657-1111
authors.initials: VL
authors.lastname: Batalha
authors.affiliation: Vascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, Georgia 30912.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Vascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, Georgia 30912.
authors.forename: Yuqing
authors.identifier: 0000-0002-0305-4122
authors.initials: Y
authors.lastname: Huo
authors.affiliation: Institute of Pharmacology and Neurosciences, Faculty of Medicine, Unit of Neurosciences, and.|Instituto de Medicina Molecular, Faculty of Medicine, University of Lisbon, 1649-028 Lisbon, Portugal, and.
authors.forename: Maria J
authors.identifier: 0000-0001-5486-6246
authors.initials: MJ
authors.lastname: Diógenes
authors.affiliation: Institute of Pharmacology and Neurosciences, Faculty of Medicine, Unit of Neurosciences, and.|Instituto de Medicina Molecular, Faculty of Medicine, University of Lisbon, 1649-028 Lisbon, Portugal, and.
authors.forename: Ana M
authors.identifier: 0000-0001-9030-6115
authors.initials: AM
authors.lastname: Sebastião
authors.affiliation: R.S. Dow Neurobiology Laboratories and dboison@downeurobiology.org.
authors.forename: Detlev
authors.identifier: 0000-0002-7740-5781
authors.initials: D
authors.lastname: Boison
mesh_terms: D000241:Adenosine / Q000378:metabolism*; D000248:Adenosine Kinase / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D001921:Brain / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009473:Neuronal Plasticity; D018377:Neurotransmitter Agents / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D013569:Synapses / Q000201:enzymology; D009435:Synaptic Transmission
chemical_list: D018377:Neurotransmitter Agents; D043705:Receptor, Adenosine A2A; D000248:Adenosine Kinase; D000241:Adenosine
keywords: adenosine kinase; epilepsy; gene mutation; human genetic disorder; learning and memory; mouse model