Metabolic regulators of nervous system development

Metabolic figure Diagram

Supervisor: Matthias Landgraf 

Project Summary (MPhil):

We discovered that metabolic signals and programmes shape neuronal function during late stages of nervous system development. Recently, we identified the highly conserved mitochondrial ROS-HIF-1alpha signalling axis as instructive during the embryonic critical period. When challenged, it causes long-term maladaptation of the nervous system, making animals seizure prone and changing behaviour. In humans, several psychiatric conditions, including schizophrenia and forms of epilepsy, have been linked to suboptimal critical periods. 

We can now use this powerful experimental system (the fruit fly) to study how these metabolic signals are regulated during embryonic development;  and how we can harness metabolic changes at later stages to re-open this unique plasticity window for corrective purposes.

Type of Work: 

You will undertake state-of-the-art genetics, and imaging using genetically encoded sensors for metabolites, and use transcriptomic methods to identify mechanisms. 

Importance of the area of research concerned:

Neurodevelopmental psychiatric conditions in humans are increasingly linked to sub-optimal critical period experiences.  This project takes a novel, metabolic perspective, which could radically change our understanding of the mechanisms that govern this unique form of neuronal plasticity. 

This knowledge should contribute toward developing therapeutic approaches that might enable re-programming neuronal properties, e.g. to ameliorate hyperexcitability of cells that causes epilepsy. 

References: 

Sobrido-Cameán D, Coulson B, Miller M, Oswald MCW, Pettini T, Bailey DMD, Baines RA, Landgraf M. Mitochondrial ROS and HIF-1α signaling mediate synaptic plasticity in the critical period (2026). PLoS Biol. 2025 Aug 13;23(8):e3003338. doi: 10.1371/journal.pbio.3003338. Epub ahead of print. PMID: 40802851.   Krick N, Davies J, Coulson B, Sobrido-Cameán D, Miller M, Oswald MCW, Zarin AA, Baines RA, Landgraf M (2024). Heterogeneous responses to embryonic critical period perturbations within the Drosophila larval locomotor circuit. bioRxiv 2024.09.14.613036; doi: https://doi.org/10.1101/2024.09.14.613036   Hunter I, Coulson B, Pettini T, Davies JJ, Parkin J, Landgraf M, Baines RA (2024). Balance of activity during a critical period tunes a developing network. eLife. 12:RP91599. doi: 10.7554/eLife.91599.