Diogenes, M. J., Neves-Tome, R., Fucile, S., Martinello, K., Scianni, M., Theofilas, P., Lopatář, Ján, Ribeiro, J. A., Maggi, L., Frenguelli, Bruno G., Limatola, C., Boison, D. and Sebastiao, A. M. (2014) Homeostatic control of synaptic activity by endogenous adenosine is mediated by adenosine kinase. Cerebral Cortex, Volume 24 (Number 1). pp. 67-80. doi:10.1093/cercor/bhs284 ISSN 1047-3211.
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Abstract
Extracellular adenosine, a key regulator of neuronal excitability, is metabolized by astrocyte-based enzyme adenosine kinase (ADK). We hypothesized that ADK might be an upstream regulator of adenosine-based homeostatic brain functions by simultaneously affecting several downstream pathways. We therefore studied the relationship between ADK expression, levels of extracellular adenosine, synaptic transmission, intrinsic excitability, and brain-derived neurotrophic factor (BDNF)-dependent synaptic actions in transgenic mice underexpressing or overexpressing ADK. We demonstrate that ADK: 1) Critically influences the basal tone of adenosine, evaluated by microelectrode adenosine biosensors, and its release following stimulation; 2) determines the degree of tonic adenosine-dependent synaptic inhibition, which correlates with differential plasticity at hippocampal synapses with low release probability; 3) modulates the age-dependent effects of BDNF on hippocampal synaptic transmission, an action dependent upon co-activation of adenosine A2A receptors; and 4) influences GABAA receptor-mediated currents in CA3 pyramidal neurons. We conclude that ADK provides important upstream regulation of adenosine-based homeostatic function of the brain and that this mechanism is necessary and permissive to synaptic actions of adenosine acting on multiple pathways. These mechanistic studies support previous therapeutic studies and implicate ADK as a promising therapeutic target for upstream control of multiple neuronal signaling pathways crucial for a variety of neurological disorders.
| Item Type: | Journal Article |
|---|---|
| Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) |
| Journal or Publication Title: | Cerebral Cortex |
| Publisher: | Oxford University Press |
| ISSN: | 1047-3211 |
| Official Date: | 2014 |
| Dates: | Date Event 2014 Published |
| Volume: | Volume 24 |
| Number: | Number 1 |
| Page Range: | pp. 67-80 |
| DOI: | 10.1093/cercor/bhs284 |
| Status: | Peer Reviewed |
| Publication Status: | Published |
| Access rights to Published version: | Restricted or Subscription Access |
| URI: | https://wrap.warwick.ac.uk/58939/ |
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