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

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 5

Epilepsy-associated cell loss.

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Epilepsy-associated cell loss. Representative micrographs of the hippoca...
Representative micrographs of the hippocampal formation from coronal brain sections taken from WT mice (A–C), fb-Adk-def mice (D–F), fb-Adk-def mice pretreated with 1 mg/kg i.p. DPCPX (G–I), and Adk-Tg mice (J–O) 24 h after intraamygdaloid injection of KA. Sections were stained either with cresyl violet or with TUNEL (green). (A–C) Typical cell death in the CA3 region of the hippocampus of WT mice ipsilateral (ipsi) to the KA-injected amygdala. (D–F) fb-Adk-def mice did not display any signs of cell loss. (G–I) After pretreatment with DPCPX, fb-Adk-def mice developed cell loss, which was comparable with WT animals. (J–O) Adk-Tg mice showed aggravated cell loss in the ipsilateral CA3 region and novel cell loss in the ipsilateral CA1 region (M), and the contralateral CA1 (N) and CA3 (O) regions. Scale bars: 300 μm (A, B, D, E, G, H, J, and K); 75 μm (C, F, I, L, M, N, and O).