Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - NEUROMET (Shaping of axonal complexity by a dynamic regulation of local metabolic pathways in the developing cortex)

Teaser

The proper function of neuronal circuits in the adult brain relies heavily on glucose metabolism to ensure energy-demanding neuronal functions such as synaptic activity or long distance axonal transport. Deregulation of the energy metabolism is strongly associated to many...

Summary

The proper function of neuronal circuits in the adult brain relies heavily on glucose metabolism to ensure energy-demanding neuronal functions such as synaptic activity or long distance axonal transport. Deregulation of the energy metabolism is strongly associated to many neurodegenerative diseases and has been linked to some neuropsychiatric diseases such as schizophrenia. However our current understanding of metabolic regulation in the developing brain and in particular in rapidly growing neurons is still fragmental.
This project aims at better understanding how a local regulation of glucose metabolism and mitochondria function underlie neuron development and circuit formation in the mouse neocortex. Our research combines live imaging of fluorescent metabolic reporters, functional metabolomics and in vivo manipulation of gene expression in mouse models to identify the relationship between glucose metabolism and axon development. Our experimental strategy tackle this question from a subcellular scale to circuits in vivo. Overall this project will expectedly provide new insights into the molecular mechanisms underlying the development of the neocortex as well as point out some of the consequences of metabolic imbalance on the development of the brain, a question that has many important implications for public health.

Work performed

The implementation of the project so far includes the purchase of all equipment required to perform the experiments including a live-imaging setup suitable for real-time imaging of the metabolic activity in developing axons. We have validated methods to measure and manipulate metabolic activity in cultured neurons and to manipulate extracellular signals tied to the local regulation of axonal morphogenesis. Furthermore we developed experimental models in vivo in the context of cortical circuits development. Especially we published findings that the NUAK1 gene is haploinsufficient in regards to cortical circuits development and demonstrated the potential pathogenicity of mutations in this gene and associated to neurodevelopmental disorders (Courchet et l., Nature Comm 2018).

Final results

This project will be continued by the implementation of methods to measure and manipulate the metabolic activity in vivo in order to correct metabolic imbalance in cortical circuits. We furthermore investigate how distinct extracellular factors converge to signaling pathways to induce the remodeling of axonal projections in callosal axons and especially how the balance between ipsilateral and contralateral projections is affected by metabolic imbalance. Overall the completion of our project will enrich our understanding of the molecular and cellular mechanisms tying the remodeling of metabolic pathways and the development of cortical connectivity.