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- Title
Adenosine Kinase Deficiency in the Brain Results in Maladaptive Synaptic Plasticity.
- Authors
Sandau, Ursula S.; Colino-Oliveira, Mariana; Jones, Abbie; Saleumvong, Bounmy; Coffman, Shayla Q.; Long Liu; Miranda-Lourenço, Catarina; Palminha, Cátia; Batalha, Vânia L.; Yiming Xu; Yuqing Huo; Diógenes, Maria J.; Sebastião, Ana M.; Boison, Detlev
- 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/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
- Subjects
ADENOSINE kinase; NEUROPLASTICITY; METHIONINE; PHENOTYPES; LABORATORY mice
- Publication
Journal of Neuroscience, 2016, Vol 36, Issue 48, p12117
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.2146-16.2016