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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/fl mice. These AdkΔbrain mice 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 A1 receptor (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 A2A receptor (A2AR) and tropomyosin-related kinase B signaling, suggesting increased activation of these receptors in synaptic plasticity phenomena. Accordingly, reducing adenosine A2A receptor activity in AdkΔbrain mice 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.
Pubmed ID: 27903722
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This polyclonal secondary targets IgG (H+L)
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View all literature mentionsThis polyclonal secondary targets IgG, IgM (H+L)
View all literature mentionsAutomation software used to analyze fear behavior in rodents. Freezing is represented in the data file in several different ways, including the total time the subject spends motionless during the session, the percent of time motionless, the number of freezing episodes or occurrences, or as an average index of motion.
View all literature mentionsWinLTP is a stimulation, data acquisition and on-line analysis electrophysiological software for studying Long-Term Potentiation (LTP), Long-term Depression (LTD), and related phenomena. WinLTP is multitasking and simultaneously runs 1) LTP stimulus/acquisition/analyzing sweeps with protocol scripting, and 2) continuous acquisition saving Axon Binary Files (abf). WinLTP runs on Windows PCI bus computers and uses National Instruments PCI M-Series boards and Axon Instruments'' Digidata 1320A and 1322A data acquisition boards. Other software that can use the M-Series boards includes Axograph Scientific''s AxoGraph X, WaveMetrics'' IGOR, National Instruments'' LabView, John Dempster''s Strathclyde Electrophysiology Suite (WinWCP and WinEDR), Silver lab''s Nclamp, and QUB data acquisition.
View all literature mentionsSoftware for image capture, processing and analysis with Leica fluorescence and confocal microscopes.
View all literature mentionsStatistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.
View all literature mentionsMus musculus with name B6.Cg-Tg(Nes-cre)1Kln/J from IMSR.
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