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Adenosine kinase is a target for the prediction and prevention of epileptogenesis in mice
Tianfu Li, … , Roger P. Simon, Detlev Boison
Tianfu Li, … , Roger P. Simon, Detlev Boison
Published January 2, 2008
Citation Information: J Clin Invest. 2008;118(2):571-582. https://doi.org/10.1172/JCI33737.
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Research Article Neuroscience Article has an altmetric score of 3

Adenosine kinase is a target for the prediction and prevention of epileptogenesis in mice

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Abstract

Astrogliosis is a pathological hallmark of the epileptic brain. The identification of mechanisms that link astrogliosis to neuronal dysfunction in epilepsy may provide new avenues for therapeutic intervention. Here we show that astrocyte-expressed adenosine kinase (ADK), a key negative regulator of the brain inhibitory molecule adenosine, is a potential predictor and modulator of epileptogenesis. In a mouse model of focal epileptogenesis, in which astrogliosis is restricted to the CA3 region of the hippocampus, we demonstrate that upregulation of ADK and spontaneous focal electroencephalographic seizures were both restricted to the affected CA3. Furthermore, spontaneous seizures in CA3 were mimicked in transgenic mice by overexpression of ADK in this brain region, implying that overexpression of ADK without astrogliosis is sufficient to cause seizures. Conversely, after pharmacological induction of an otherwise epileptogenesis-precipitating acute brain injury, transgenic mice with reduced forebrain ADK were resistant to subsequent epileptogenesis. Likewise, ADK-deficient ES cell–derived brain implants suppressed astrogliosis, upregulation of ADK, and spontaneous seizures in WT mice when implanted after the epileptogenesis-precipitating brain injury. Our findings suggest that astrocyte-based ADK provides a critical link between astrogliosis and neuronal dysfunction in epilepsy.

Authors

Tianfu Li, Gaoying Ren, Theresa Lusardi, Andrew Wilz, Jing Q. Lan, Takuji Iwasato, Shigeyoshi Itohara, Roger P. Simon, Detlev Boison

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Figure 2

Generation and characterization of fb-Adk-def mice.

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Generation and characterization of fb-Adk-def mice.
               
(A) ...
(A) The short isoform of mouse Adk cDNA is located between a human ubiquitin promoter (hUbi) and an SV40 polyA sequence. The UbiAdk transgene is flanked by loxP sites. (B) Adk-Tg mice, which were homozygous for the Adk-KO and the TgUbiAdk transgene, were bred with fb-Adk-def mice, which were heterozygous for Cre. From these crosses, Adk-Tg and fb-Adk-def littermates were produced. (C) Representative PCR of selected animals. Tg, Adk-Tg; def, fb-Adk-def. DNA was amplified with a PCR specific for either the WT (640 bp) or the KO allele (840 bp) of the endogenous Adk gene (Adk-PCR), a PCR specific for the Adk transgene (Tg-PCR), giving rise to a 420-bp amplification product, or a PCR specific for the Cre gene (Cre-PCR), giving rise to a 600-bp product. (D) Representative western blot from adult WT, fb-Adk-def, and Adk-Tg mice. Top: ADK-immunoreactive bands from forebrain (fb) or brainstem plus cerebellum (bs-cb). Bottom: β-Actin–immunoreactive bands were used to normalize for equal loading. (E) Quantitative analysis of ADK levels based on 3 western blots performed with samples from n = 2 animals from each genotype. ADK levels were first normalized to equal loading according to the β-actin standard. These values were then normalized to the respective WT samples (set as 100%). Data represent the mean ± SD of 6 samples. *P < 0.05; **P < 0.01, paired comparisons in t test.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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