Human Frontiers Science Program (HFSP)
About the Project
The main aim of the present project was to investigate the role of astroglial mitochondrial G protein (mtG) signalling in brain physiology, identifying the underlying cellular, network, behavioural and theoretical modelling mechanisms.
The project proposes to artificially manipulate mtG signalling by generating novel pharmacogenetic tools (DREADDs specifically expressed by astroglial mitochondria, astro-mtDREADDs) that will allow the specific control of astroglial mtG protein activity.
The project will also investigate the role of a physiologically relevant modulator of mtG signalling, such as the G Protein-Coupled Cannabinoid Receptor (CB1), which is partially localized on brain mitochondria, including of astroglial cells, where it can modulate mitochondrial functions.
Thus, this project aimed at experimentally and theoretically analyzing the consequences of activation of different mtG proteins (via mtDREADDs or mtCB1 receptors) on neuronal, synaptic, and network activity as well as brain functions in living animals.
In addition, to compare with specific mitochondrial functions, part of the project was dedicated to the study of general astroglial impact onto brain physiology, both from the experimental and computational points of view.
Projected key outcomes
- A complete model of mitochondria function showing through simulations that Ca2+ uptake by mitochondria requires the activation of CB1Rs on both the astrocyte plasma membrane and the OMM at the same time
- A biophysical model of mitochondrial Ca2+ uptake as a response to CB1 receptor stimulation on both the astrocyte membrane and outer membrane of the mitochondria
- Journal Publication: "GABA Regulation of Burst Firing in Hippocampal Astrocyte Neural Circuit: A Biophysical Model",
Junxiu Liu, Liam McDaid, Alfonso Araque, John Wade, Jim Harkin, Shvan Karim, David C Henshall, Niamh M C Connolly, Anju P Johnson, Andy M Tyrrell, Jon Timmis, Alan G Millar, James Hilder and David M Halliday, Front Cell Neurosci. July 23rd 2019