Adenosine dysfunction in astrogliosis: Cause for seizure generation?

Tianfu Li, Jing Quan Lan, Bertil B. Fredholm, Roger P. Simon, Detlev Boison

Research output: Contribution to journalArticlepeer-review

85 Scopus citations

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 A 1 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.

Original languageEnglish (US)
Pages (from-to)353-366
Number of pages14
JournalNeuron Glia Biology
Volume3
Issue number4
DOIs
StatePublished - Nov 2007
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Cellular and Molecular Neuroscience
  • Cell Biology

Keywords

  • A receptor
  • Astrocyte
  • Epileptogenesis
  • Kainic acid
  • Status epilepticus

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