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 8

Histological assessment of the antiepileptogenic effect of Adk–/– ES cell–derived NPs assessed on coronal brain sections of mice 3 weeks after KA injection/cell transplantation.

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Histological assessment of the antiepileptogenic effect of Adk–/– ES cel...
First column: Sham-treated KA-injected control animals. Second column: KA-treated recipients of WT cells. Third column: KA-treated recipients of Adk–/– ES cell–derived NPs. Fourth column: untreated control animals. (A–D) Cresyl violet staining demonstrating CA3 selective neuronal cell loss in all KA-injected animals. (E–H) GFAP immunofluorescence showing prominent CA3 gliosis in sham-treated and WT KA-injected animals, reduced gliosis in Adk–/– NP recipients, and lack of gliosis in untreated controls. (I–L) ADK immunofluorescence showing prominent upregulation of ADK in the KA-injected control animals but lack of ADK upregulation in Adk–/– NP recipients. (M–P) Overlay of GFAP and ADK immunofluorescence. (Q–T) Confocal analysis of GFAP and ADK immunofluorescence showing overexpression and redistribution of ADK (red) in the context of gliosis (green) in the KA-injected sham-treated and WT controls but not in the Adk–/– NP recipients. For comparison, an astrocyte from the stratum radiatum of an untreated control animal is shown (T), since no astrocytes are normally located within the CA3. Scale bars: 75 μm (A–P); 10 μm (Q–T).