Brain Advance Access originally published online on June 1, 2005
Brain 2005 128(10):2383-2395; doi:10.1093/brain/awh555
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Astrogliosis in epilepsy leads to overexpression of adenosine kinase, resulting in seizure aggravation
1 Institute of Pharmacology and Toxicology, University of Zurich, 2 Institute of Pharmaceutical Sciences, Federal Institute of Technology (ETH) and 3 Biological Central Laboratory, University of Zurich, Zurich, Switzerland
Correspondence to: Detlev Boison, Institute of Pharmacology and Toxicology, University of Zurich, CH-8057 Zurich, Switzerland. E-mail: boison{at}pharma.unizh.ch
Adenosine kinase (ADK) is considered to be the key regulator of the brain's endogenous anticonvulsant, adenosine. In adult brain, ADK is primarily expressed in a subpopulation of astrocytes and striking upregulation of ADK in these cells has been associated with astrogliosis after kainic acid-induced status epilepticus (KASE) in the kainic acid mouse model of temporal lobe epilepsy. To investigate the causal relationship between KASE-induced astrogliosis, upregulation of ADK and seizure activity, we have developed a novel mouse model [the Adktm1–/–-Tg(UbiAdk) mouse] lacking the endogenous astrocytic enzyme due to a targeted disruption of the endogenous gene, but containing an Adk transgene under the control of a human ubiquitin promoter. Mutant Adktm1–/–-Tg(UbiAdk) mice were characterized by increased brain ADK activity and constitutive overexpression of transgenic ADK throughout the brain, with particularly high levels in hippocampal pyramidal neurons. This ADK overexpression was associated with increased baseline levels of locomotion. Most importantly, two-thirds of the mutant mice analysed exhibited spontaneous seizure activity in the hippocampus and cortex. This was the direct consequence of transgene expression, since this seizure activity could be prevented by systemic application of the ADK inhibitor 5-iodotubercidin. Intrahippocampal injection of kainate in the mutant mice resulted in astrogliosis to the same extent as that observed in wild-type mice despite the absence of endogenous astrocytic ADK. Therefore, KASE-induced upregulation of endogenous ADK in wild-type mice is a consequence of astrogliosis. However, seizures in kainic acid-injected mutants displayed increased intra-ictal spike frequency compared with wild-type mice, indicating that, once epilepsy is established, increased levels of ADK aggravate seizure severity. We therefore conclude that therapeutic strategies that augment the adenosine system after astrogliosis-induced upregulation of ADK constitute a neurochemical rationale for the prevention of seizures in epilepsy.
Key Words: adenosine; adenosine kinase; epilepsy; astrogliosis; transgenic mice
Abbreviations: A1R = adenosine A1 receptor; ADK = adenosine kinase; DPCPX = 8-cyclopentyl-1,3-dipropyl-xanthine; EPSC = excitatory postsynaptic current; GFAP = glial fibrillary acidic protein; ITU = 5-iodotubercidin; KA = kainic acid; KASE = kainic acid-induced status epilepticus; LCCG1 = (2S,1'S,2'S)-2-carboxycyclopropyl) glycine; NBQX = 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulphonamide; Tg = transgenic
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Received February 7, 2005. Revised April 29, 2005. Accepted May 6, 2005.
* These authors contributed equally to this work
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