Analysis of the metabolic homeostasis of the Drosophila brain

• Applicant: Professorin Dr. Stefanie Schirmeier
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2016 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 313812978

• Final Report Year: 2021

Final Report Abstract

The nervous system consumes large amounts of energy that need to be efficiently delivered. Since neuronal function also depends on a strictly controlled extracellular milieu, neurons are well separated from circulation by the blood-brain barrier. This, in turn, necessitates efficient ways of supplying nutrients, which means strictly regulated transport. During the funding period we addressed the question via which transporters carbohydrate transport at the BBB is achieved and how it is regulated. We found that at least three different transporter proteins, capable of transporting trehalose and glucose, are expressed at the BBB. The expression of those proteins is dynamically regulated and adapted to different conditions, e.g. loss of one transporter or starvation. The TGFß-pathway is implicated in the regulation of transporter expression at the BBB. We further aimed to analyze metabolite fluxes in the nervous system. To this end we generated flies expressing different genetically encoded metabolite sensors. We analyzed the functionality of those metabolite sensors and used the FRET-based glucose sensor, FLII12Pglu-700µδ6, successfully to analyze different aspects of carbohydrate transport. We further showed that the pyruvate sensor, PyronicSF, can be used to analyze cytosolic and mitochondrial pyruvate levels in Drosophila. We will use this sensor in the future to analyze pyruvate turnover in the different cell types in the nervous system to gain further insights into the metabolic coupling between glial cells and neurons. The results obtained within the funding period led to the publication of several peer-reviewed articles.

Publications

• (2017) Insect models of central nervous system energy metabolism and its links to behavior. Glia 66: 1160–1175
  Rittschof CC & Schirmeier S
  
• (2017) Metabolite transport across the mammalian and insect brain diffusion barriers. Neurobiol. Dis. 107: 15–31
  Weiler A, Volkenhoff A, Hertenstein H & Schirmeier S
  
• (2018) Live imaging using a FRET glucose sensor reveals glucose delivery to all cell types in the Drosophila brain. J. Insect Physiol. 106: 55–64
  Volkenhoff A, Hirrlinger J, Kappel JM, Klämbt C & Schirmeier S
  
• (2020) A highly responsive pyruvate sensor reveals pathway-regulatory role of the mitochondrial pyruvate carrier MPC. Elife 9: e53917
  Arce-Molina R, Cortés-Molina F, Sandoval PY, Galaz A, Alegría K, Schirmeier S, Barros LF & San Martín A
  
• (2020) Highly responsive singlefluorophore indicator to explore lactate dynamics in high calcium environments
  Galaz A, Sandoval PY, Soto-Ojeda I, Hertenstein H, Schweizer J, Schirmeier S, Barros LF & San Martín A
  
• (2021) Plasticity of Carbohydrate Transport at the Blood-Brain Barrier. Front. Behav. Neurosci. 14: 271
  McMullen E, Weiler A, Becker HM & Schirmeier S
  
• (2021) Starvation-induced regulation of carbohydrate transport at the blood–brain barrier is TGF-β-signaling dependent. Elife 10: e62503
  Hertenstein H, McMullen E, Weiler A, Volkenhoff A, Becker HM & Schirmeier S