Journal
NEURON GLIA BIOLOGY
Volume 3, Issue -, Pages 353-366Publisher
CAMBRIDGE UNIV PRESS
DOI: 10.1017/S1740925X0800015X
Keywords
epileptogenesis; kainic acid; status epilepticus; A(1) receptor; astrocyte
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Funding
- NINDS NIH HHS [R21 NS057475, R01 NS058780-01A1, R21 NS057538, R21 NS057475-01A2, R01 NS058780, R21 NS057538-01A2] Funding Source: Medline
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R21NS057475, R01NS058780, R21NS057538] Funding Source: NIH RePORTER
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Epilepsy is characterized by both ilcuronal and astroglial dysfunction. The endogenous anticonvulsont adcnosine, 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 cornprchcsivc approach that includes a new mouse model offocal epileptogenesis, mutant mice with altered brain levels of adenosille, and mice lacking adenosine A, receptors. In wild-typc mice, following a focal epileptogetiesisprecipitating injury, astrogliosis, upregulation of the adenosine-removing astrocytic enzyme adenosille killase (ADK), and spontaneous seizures coincide in a spatio-temporally restricted manner. Importantly, these spontaneous seizures tire mimicked by untreated transgcnic micc that either overexpress ADK in brain at- lack A, 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, rcceptor-mediated modulation of neuronal excitability, and support the ADK hypothesis of epileptogenesis in which uprcgulation 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.
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