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Adenosine dysfunction in astrogliosis: cause for seizure generation?

Published online by Cambridge University Press:  07 July 2008

Tianfu Li
Affiliation:
RS Dow Neurobiology Laboratories, Legacy Research, Portland, OR 97232, USA
Jing Quan Lan
Affiliation:
RS Dow Neurobiology Laboratories, Legacy Research, Portland, OR 97232, USA
Bertil B. Fredholm
Affiliation:
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
Roger P. Simon
Affiliation:
RS Dow Neurobiology Laboratories, Legacy Research, Portland, OR 97232, USA
Detlev Boison
Affiliation:
RS Dow Neurobiology Laboratories, Legacy Research, Portland, OR 97232, USA

Abstract

Epilepsy is characterized by both neuronal and astroglial dysfunction. The endogenous anticonvulsant adenosine, the level of which is largely controlled by astrocytes, might provide a crucial link between astrocyte and neuron dysfunction in epilepsy. Here we have studied astrogliosis, a hallmark of the epileptic brain, adenosine dysfunction and the emergence of spontaneous seizures in a comprehensive approach that includes a new mouse model of focal epileptogenesis, mutant mice with altered brain levels of adenosine, and mice lacking adenosine A1 receptors. In wild-type mice, following a focal epileptogenesis-precipitating injury, astrogliosis, upregulation of the adenosine-removing astrocytic enzyme adenosine kinase (ADK), and spontaneous seizures coincide in a spatio-temporally restricted manner. Importantly, these spontaneous seizures are mimicked by untreated transgenic mice that either overexpress ADK in brain or lack A1 receptors. Conversely, mice with reduced ADK in the forebrain do not develop either astrogliosis or spontaneous seizures. Our studies define ADK as a crucial upstream regulator of A1 receptor-mediated modulation of neuronal excitability, and support the ADK hypothesis of epileptogenesis in which upregulation of ADK during astrogliosis provides a crucial link between astrocyte and neuron dysfunction in epilepsy. These findings define ADK as rational target for therapeutic intervention.

Type
Research Article
Copyright
Copyright © Cambridge University Press 2008

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