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 1

Characterization of spontaneously epileptic mice 3 weeks after intraamygdaloid injection of KA.

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Characterization of spontaneously epileptic mice 3 weeks after intraamyg...
(A–D) Representative cresyl violet–stained coronal brain section showing the hippocampal formation contralateral (A and C) or ipsilateral (B and D) to the KA injection. Note the CA3 selective cell loss in the ipsilateral hippocampus (B and D). (E and F) Adjacent coronal brain section from the same animal stained with the nuclear stain DAPI showing an increase in the number of cell nuclei in the injured CA3. (G and H) The same section stained with NFM indicating the presence of dense neuronal networks within the injured CA3. (I–N) ADK immunoreactivity within the hippocampal formation visualized with diaminobenzidine contralateral (I, K, and M) or ipsilateral (J, L, and N) to the KA injection. Note the focal overexpression of ADK in the ipsilateral CA3. I–L are from the same animal and adjacent to those shown in A–H. M and N are derived from the same animal at a more caudal location, representing the level of cell transplantations (see Figure 10). Arrows in J and N point to upregulated ADK in ipsilateral CA3. (O–R) Confocal analysis of ADK (red) and GFAP (green) immunoreactivity in the contralateral (O and P) and ipsilateral (Q and R) CA3. Note prominent astrogliosis (GFAP) and overexpression and redistribution of ADK in the ipsilateral CA3 (Q and R). Bottom: Representative EEG recordings obtained from electrodes inserted into the ipsilateral CA3 or CA1 or placed onto the cortex. Scale bars: 300 μm (A, B, I, J, M, and N), 75 μm (C and D), 37.5 μm (E, F, G, H, K, and L), 12 μm (O and Q), and 5 μm (P and R). EEG scale bar: 2 s.