TY - JOUR
T1 - Adenosine kinase deficiency in the brain results in maladaptive synaptic plasticity
AU - Sandau, Ursula S.
AU - Colino-Oliveira, Mariana
AU - Jones, Abbie
AU - Saleumvong, Bounmy
AU - Coffman, Shayla Q.
AU - Liu, Long
AU - Miranda-Lourenço, Catarina
AU - Palminha, Cátia
AU - Batalha, Vânia L.
AU - Xu, Yiming
AU - Huo, Yuqing
AU - Diógenes, Maria J.
AU - Sebastião, Ana M.
AU - Boison, Detlev
N1 - Funding Information:
This work was supported by the National Institutes of Health (Grants MH083973, NS088024, and HL09556) and the Fundação para a Ciência e Tecnologia (FTC Grant EXPL/BIM-MEC/0009/2013). M.C.-O. was funded by FCT Fellowship SFRH/BD/73276/2010.
Publisher Copyright:
© 2016 the authors.
PY - 2016/11/30
Y1 - 2016/11/30
N2 - 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 Adk brain 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 syn-apses 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 Adk∆brain 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.
AB - 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 Adk brain 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 syn-apses 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 Adk∆brain 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.
KW - Adenosine kinase
KW - Epilepsy
KW - Gene mutation
KW - Human genetic disorder
KW - Learning and memory
KW - Mouse model
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U2 - 10.1523/JNEUROSCI.2146-16.2016
DO - 10.1523/JNEUROSCI.2146-16.2016
M3 - Article
C2 - 27903722
AN - SCOPUS:85006024470
SN - 0270-6474
VL - 36
SP - 12117
EP - 12128
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 48
ER -