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

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 6

Assessment of epileptogenesis 3 weeks after KA/SE.

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Assessment of epileptogenesis 3 weeks after KA/SE. Representative microg...
Representative micrographs and EEGs taken from the hippocampal formation of WT mice (A), fb-Adk-def mice (B), and fb-Adk-def mice pretreated with 1 mg/kg i.p. DPCPX (C) 3 weeks after intraamygdaloid injection of KA. First row: Cresyl violet–stained sections showing the characteristic ipsilateral KA/SE-induced CA3 lesion in WT and fb-Adk-def/DPCPX mice (A and C, asterisks), but not in fb-Adk-def mice. Insets show enlarged ipsilateral CA3 (magnification, ×2.25). Second row: ADK immunoreactivity visualized with DAB. Note that ADK is exclusively upregulated in the ispsilateral CA3 of WT animals, corresponding to the location of the primary brain injury (arrow). Third row: GFAP immunofluorescence staining showing astrogliosis in the ipsilateral CA3 of WT mice but lack of astrogliosis in fb-Adk-def and fb-Adk-def/DPCPX mice. Fourth row: ADK immunofluorescence staining of the same specimen. Fifth row: Overlay of GFAP (green) and ADK (red) immunofluorescence showing colocalization (yellow) of GFAP and ADK in the astrogliotic CA3 region of WT mice. Sixth row: Representative intrahippocampal EEG recordings taken from CA3 recordings showing spontaneous focal seizures in WT animals, while fb-Adk-def and fb-Adk-def/DPCPX mice were protected from the development of spontaneous seizures. Scale bars: 300 μm (black bars); 75 μm (white bars). EEG scale bar: 10 s.