AMP-Activated Protein Kinase Links Neuronal Remodeling to Metabolic Control

• Applicant: Dr. Sebastian Rumpf
• Subject Area: Developmental Neurobiology ; Cell Biology
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 389427334

• Final Report Year: 2023

Final Report Abstract

In order to specify neuronal circuits during development, many neurons remodel their neurites and synapses through pruning and subsequent regrowth. Pruning and regrowth occur at specific developmental stages that are often defined through hormones. For example, synaptic pruning occurs in mice during a primary phase of brain circuit refinement and a secondary phase during adolescence. Similarly, synapse and neurite pruning occurs at large scale during metamorphosis in Drosophila. The cell-autonomous neuronal signaling leading to neuronal remodeling must therefore be coordinated with the development status of the surrounding tissue or even the whole organism. We found that loss of the AMP-activated protein kinase (AMPK) causes cell-autonomous dendrite pruning defects in peripheral sensory class IV dendritic arborization (c4da) neurons in Drosophila. AMPK is a well-known regulator of energy homeostasis that restores ATP levels upon energy stress by suppressing anabolic pathways and activating catabolic ones. Using FRET-based biosensors, we found that AMPK is under control of the pupariation hormone ecdysone during the pupal stage. Furthermore, loss of AMPK caused c4da neurons to shift ATP production from oxidative phosphorylation to glycolysis. During early metamorphosis, the amount of circulating sugars in the hemolymph is reduced, necessitating the use of other fuels such as amino acids for energy production. Consistently, the c4da neuron dendrite pruning defects upon loss of AMPK are synergistically enhanced by low amino acid levels in the food. Under these conditions, stage-specific pruning factors are not expressed properly anymore in c4da neurons. We conclude that the pupariation hormone ecdysone adapts neuronal metabolism to the specific energy demands of the early pupal stage to ensure that the developmental pruning programme can be carried out.

Publications

• AMPK adapts metabolism to developmental energy requirement during dendrite pruning in Drosophila. Cell Reports, 37(7), 110024.
  Marzano, Marco; Herzmann, Svende; Elsbroek, Leonardo; Sanal, Neeraja; Tarbashevich, Katsiaryna; Raz, Erez; Krahn, Michael P. & Rumpf, Sebastian
  
• Neurofly 2022 – 19th European Drosophila Neurobiology Conference. „Metabolic Regulation of Dendrite Pruning.“ St. Malo, France, September 2022
  Marco Marzano
  
• Energy metabolic pathways in neuronal development and function. Oxford Open Neuroscience, 2(2023).
  Rumpf Sebastian; Sanal Neeraja & Marzano Marco