Laboratory of Neuroenergetics and Psychiatric Diseases
PROF. PIERRE J. MAGISTRETTI
The research unit of Prof. Pierre Magistretti is dedicated to studying the role of astrocytes, neuroenergetics and neurometabolic coupling in psychiatric diseases and addiction.
Previous work from Magistretti’s laboratory have shown that under metabolic demand, neurons signal to astrocytes to undergo two different mechanisms to provide a source of energy, 1- increased glycogenolysis (energy reserve found solely in astrocytes) or 2-increased aerobic glycolysis. Activation of these pathways produce lactate which can be used as a source of energy for neurons. This mechanism, referred as Astrocyte Neuron Lactate Shuttle (ANLS), is shown to be involved in basic neuro-physiological functions such as learning and memory and across sleep-wake cycle.
Given that patients with psychiatric diseases show losses in astrocyte numbers and have impairments in glucose utilizations, we hypothesize that a dysfunction of this brain energy metabolic coupling could play a role in the etiology of the illnesses.
- Impact of various antidepressants drug on brain energy metabolism in vitro.
- Involvement of brain energy metabolism in antidepressant effects of pharmacological or environmental manipulations (sleep deprivation, stress) in vivo.
- Role of brain energy metabolism in animal models of addiction (rodents).
These projects are carried out in collaboration with Drs Benjamin Boutrel, Jean-Luc Martin, Jean-René Cardinaux and Jean-Marie Petit at the CNP. Axis 1 and 2 are performed in the framework of the « Pôle de Recherche National (PRN) Synapsy, (NCCR “The synaptic bases of the mental diseases”) funded by the “Fonds National Suisse de la Recherche Scientifique” and supported by the "Fondation Préfargier".
- Examining the impact of various antidepressants drugs on brain energy metabolism in vitro.
Cell cultures of astrocytes and neurons represent a good strategy to study the impact of antidepressants on brain energy metabolism and to dissect out the mechanism of action in different cell types. Towards the end of the experiment, cells and their media are harvested and evaluated for their metabolic, kinetic and molecular profiles using specific assays designed towards each end.
- Determining the involvement of brain energy metabolism in antidepressant effects of pharmacological or environmental manipulations in vivo.
Biosensor is a highly sensitive technique with a great time resolution and is used to detect brain metabolic products in freely moving animals.
Upon the insertion of a probe, we can compare the impact of antidepressants on different metabolic products of interest over time.
In addition, modulation of brain energy metabolism via pharmacological (i.e cerebral microinjection or peripheral injections of various pharmacological drugs) or environmental manipulations (i.e. exercise) are also carried out and their effects are tested in different behavioral models of despair (i.e Forced Swim Test) and anhedonia (i.e Sucrose Consumption Test). Ultimately, the brains are then harvested for further molecular and cellular characterizations using techniques such as qPCR, immunohistochemistry and western blot. Furthermore, by coupling the use of FACS technique with transgenic mice expressing GFP under the control of different cell specific promoters, we are also developing a new methodology designed to determine the cellular targets of antidepressants.
- Determining the involvement of brain energy metabolism in animal models of addiction
Similarly, biosensors, molecular (such as qPCR) and behavioral techniques (such as place preference test) are also used to study the involvement of brain energy metabolism in animal models of addiction.
- In Vivo Evidence for a Lactate Gradient from Astrocytes to Neurons.
Mächler P, Wyss MT, Elsayed M, Stobart J, Gutierrez R, von Faber-Castell A, Kaelin V, Zuend M, San Martín A, Romero-Gómez I, Baeza-Lehnert F, Lengacher S, Schneider BL, Aebischer P, Magistretti PJ, Barros LF, Weber B.
Cell Metab. 2016 Jan 12;23(1):94-102. doi: 10.1016/j.cmet.2015.10.010.
- Channel-mediated lactate release by K⁺-stimulated astrocytes.
Sotelo-Hitschfeld T, Niemeyer MI, Mächler P, Ruminot I, Lerchundi R, Wyss MT, Stobart J, Fernández-Moncada I, Valdebenito R, Garrido-Gerter P, Contreras-Baeza Y, Schneider BL, Aebischer P, Lengacher S, San Martín A, Le Douce J, Bonvento G, Magistretti PJ, Sepúlveda FV, Weber B, Barros LF.
J Neurosci. 2015. 35(10):4168-78. doi: 10.1523/JNEUROSCI.5036-14.2015.
- Cerebral metabolic effects of exogenous lactate supplementation on the injured human brain.
Bouzat P, Sala N, Suys T, Zerlauth JB, Marques-Vidal P, Feihl F, Bloch J, Messerer M, Levivier M, Meuli R, Magistretti PJ, Oddo M.
Intensive Care Med. 2014. 40(3):412-21. doi: 10.1007/s00134-013-3203-6.