Regulation of tonic currents through changes in extracellular GABA. (360G-Wellcome-083163_Z_07_Z)

Tonic GABA(A) receptor currents play a major role in controlling neuronal and network excitability. Their magnitude depends on the concentration of extracellular GABA, the regulation and sources of which are still unclear. The aims of this project are to determine the sources for and regulation of extracellular GABA that modulate tonic currents in the hippocampus. Our key goals are to address six hypotheses: 1) Variations in synaptic GABA release affect the tonic current 2) Extracellular GABA is released from astrocytes, 3) Glutamate uptake contributes to the extracellular GABA pool 4) GAD65 contributes to the extracellular GABA pool 5) Rises in extracellular GABA during physiological activity in vivo are secondary to changes in GABA uptake 6) Extracellular GABA varies diurnally and is associated with changes in behavioural state We will take two separate but complimentary approaches and take advantage of expertise in London (patch clamp, EEG), Bristol (in vivo microdialysi s) and Japan (confocal imaging of astrocytes). We will address the question of the potential sources for extracellular GABA using in vitro hippocampal slice preaparations, and we will use an in vivo approach to determine the regulation of extracellular GABA during different physiological states.