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The role of resting Ca2+ in astrocyte Ca2+ signalling

King, CM; (2016) The role of resting Ca2+ in astrocyte Ca2+ signalling. Doctoral thesis , UCL (University College London). Green open access

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Abstract

Astrocytes form gap-junction coupled networks and their fine processes cover many synapses enabling astrocytes to powerfully modulate synapse function. Such modulation is thought to involve Ca2+ -dependent release of signalling molecules from astrocytes. However, astrocyte Ca2+ signalling and its role in synaptic physiology remains a matter of debate. An incomplete and mostly qualitative understanding of the fundamental mechanisms of intracellular Ca2+ signalling in astrocytes could be a knowledge-limiting factor. Previous studies predict that astrocyte resting [Ca2+] profoundly affects astrocyte Ca2+ signalling, especially IP3 and store-dependent Ca2+ transients. I therefore quantitatively investigated the role of resting [Ca2+] in shaping spontaneous and evoked Ca2+ transients in astrocytes. I used two-photon excitation fluorescence microscopy and whole-cell patch clamp to document Ca2+ signalling of individual passive astrocytes in the CA1 stratum radiatum of acute hippocampal slices in young adult rat. I used fluorescence lifetime imaging to obtain a quantitative readout of astrocyte [Ca2+] and reveal the relationship between resting [Ca2+] and Ca2+ transients. I combined these techniques with UV-uncaging of Ca2+ or Ca2+ buffer to manipulate the astrocyte resting [Ca2+] to further investigate its effect on Ca2+ signalling. Using these methods, we have found that low resting [Ca2+] were associated with smaller amplitudes of spontaneous Ca2+ transients. This was also true for metabotropic glutamate receptor agonist (DHPG) evoked Ca2+ transients when different cells or regions of interest of the same cell were compared. The well-established increase of most IP3 receptors’ open probability at higher cytosolic [Ca2+] could explain this observation. In contrast, changes of resting [Ca2+] within a single astrocyte region were associated with inverse changes in amplitude of evoked Ca2+ transients. The DHPG-induced equilibration of [Ca2+] across cytosol and store compartments could be a potential explanation for this effect. Thus, resting [Ca2+] could shape the amplitude of astrocyte Ca2+ transients by at least two distinct mechanisms.

Type: Thesis (Doctoral)
Title: The role of resting Ca2+ in astrocyte Ca2+ signalling
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Keywords: astrocyte, calcium, Fluorescence lifetime imaging, DHPG, hippocampus, Oregon Green BAPTA
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Experimental Epilepsy
URI: http://discovery.ucl.ac.uk/id/eprint/1474498
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