Microglia action towards neuronal circuit formation and function in health and disease

Title Microglia action towards neuronal circuit formation and function in health and disease
Website http://ist.ac.at/research/life-sciences/siegert-group/
Start date 2017-03-01
End date 2022-02-28
Sponsor European Research Council - Starting Grant (ERC-StG)

Associated cell lines

Project Description

Constructing a neuronal circuit requires a firework of developmental events: The desired cell types have to be generated and wired correctly. Random propagating bursts of action potentials between neighboring cells shape the functional maturation of these cell types, which will be activity-dependently refined later. Microglia are exposed to this environment from the beginning and show a morphologically “alerted”, phagocytic state throughout development. However, microglia have been proven to be involved in synapse refinement, which leads to the question how do microglia know when to alter neuronal circuit elements during development without inducing circuit malfunction? This is a fundamental question, because alerted microglia during development are intriguingly similar to alerted microglia in neurodegenerative diseases. To address this question, I will use the retina as a model system and propose the following three aims: First, we will reveal how the functional and gene regulatory network of alerted microglia adapts to spontaneous neuronal activity-dependent developmental events, and identify how, in return, microglia influence circuit formation and function. Second, we will examine the dynamics of alerted microglia upon sequential removal of neuronal cell types under disease conditions, and investigate whether functional restoration of cell types using optogenetic techniques resets microglia function into the surveying state. Third, we will establish the role of healthy and diseased microglia in human retinal circuit formation by reprogramming microglia and 3D retinoids from healthy and diseased human iPS cells. We predict that our findings will provide novel and crucial insights into the functional impact of microglia upon both normal neuronal circuit development and function, as well as how their actions lead to disease phenotypes in situations of neurodevelopmental and neurodegenerative diseases.