Adenosine kinase is a target for the prediction and prevention of epileptogenesis in mice
Open Access
- 2 January 2008
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 118 (2), 571-582
- https://doi.org/10.1172/JCI33737
Abstract
Astrogliosis is a pathological hallmark of the epileptic brain. The identification of mechanisms that link astrogliosis to neuronal dysfunction in epilepsy may provide new avenues for therapeutic intervention. Here we show that astrocyte-expressed adenosine kinase (ADK), a key negative regulator of the brain inhibitory molecule adenosine, is a potential predictor and modulator of epileptogenesis. In a mouse model of focal epileptogenesis, in which astrogliosis is restricted to the CA3 region of the hippocampus, we demonstrate that upregulation of ADK and spontaneous focal electroencephalographic seizures were both restricted to the affected CA3. Furthermore, spontaneous seizures in CA3 were mimicked in transgenic mice by overexpression of ADK in this brain region, implying that overexpression of ADK without astrogliosis is sufficient to cause seizures. Conversely, after pharmacological induction of an otherwise epileptogenesis-precipitating acute brain injury, transgenic mice with reduced forebrain ADK were resistant to subsequent epileptogenesis. Likewise, ADK-deficient ES cell-derived brain implants suppressed astrogliosis, upregulation of ADK, and spontaneous seizures in WT mice when implanted after the epileptogenesis-precipitating brain injury. Our findings suggest that astrocyte-based ADK provides a critical link between astrogliosis and neuronal dysfunction in epilepsy.Keywords
This publication has 46 references indexed in Scilit:
- Lentiviral RNAi-induced downregulation of adenosine kinase in human mesenchymal stem cell grafts: A novel perspective for seizure controlExperimental Neurology, 2007
- Suppression of kindling epileptogenesis by adenosine releasing stem cell-derived brain implantsBrain, 2007
- Astrocyte Control of Synaptic Transmission and Neurovascular CouplingPhysiological Reviews, 2006
- Adenosine A1 receptors are crucial in keeping an epileptic focus localizedExperimental Neurology, 2006
- Adenosine and ATP Link PCO2 to Cortical Excitability via pHNeuron, 2005
- Repair of the Injured Adult Hippocampus through Graft-Mediated Modulation of the Plasticity of the Dentate Gyrus in a Rat Model of Temporal Lobe EpilepsyJournal of Neuroscience, 2005
- Adenosine A1 Receptor Knockout Mice Develop Lethal Status Epilepticus after Experimental Traumatic Brain InjuryJournal of Cerebral Blood Flow & Metabolism, 2005
- Epileptogenesis and chronic seizures in a mouse model of temporal lobe epilepsy are associated with distinct EEG patterns and selective neurochemical alterations in the contralateral hippocampusExperimental Neurology, 2005
- Dorsal telencephalon‐specific expression of Cre recombinase in PAC transgenic micegenesis, 2004
- Loss of A1 adenosine receptors in human temporal lobe epilepsyBrain Research, 1996