Adenosine dysfunction in astrogliosis: cause for seizure generation?

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.