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

Periodic Reporting for period 2 - MICROGLIA-CIRCUIT (Microglia action towards neuronal circuit formation and function in health and disease)

Reporting period: 2018-11-01 to 2020-04-30

The brain is assembled from thousands of cell types, which are functionally organized in neuronal circuits to collect, encode and process environmental information, resulting in a behavior outcome. The correct circuit assembly is crucial for preventing malfunction. Classical studies have provided important insights into the necessity of correct neuron wiring, but a detailed understanding of the role of microglia is missing. Microglia are traditionally categorized as immune-responsive, but are also involved in cell removal and synapse refinement. The goal of this project is to provide an answer to the important question: How microglia interact with other cell types and sense changes during neuronal circuit development, maintenance and degeneration? Thus, we will elucidate the key molecular and genetic principles underlying microglial phenotype during neuronal circuit formation, identify the circuit components with which microglia are interacting with at a spatial-temporal resolution, pin-point how neuronal activity alters microglial function, and finally differentiate human pluripotent stem cells into microglia to develop a strategy to address microglia-associated disease genes in neurodevelopmental diseases.

The knowledge is fundamental for the society because microglia are frequently found in a phagocytic-associated state in post-mortem human brain of neurodevelopmental disease such as autism spectrum disorder and schizophrenia as well as neurodegenerative diseases. Furthermore, several disease-associated genes are expressed exclusive expressed in microglia. Therefore, microglial malfunction could lead to similar devastating effects as neuronal circuit malfunction. It is critical that we know which cell type to address at which time point.

The overall objectives cover to identify the different states of microglial activation on the morphological and transcriptional level. Then, we are manipulating microglia or neurons and see how they impact each other. And finally, we will translate our observations to the human microglia model system.
1. We are proposing a new classifier that will allow to uniquely analyse microglia. For this, we have generated a library of over 30’000 traced microglia in different developmental and disease progression states in various brain regions for both sexes. We are now applying a quantitative morphometric analysis of microglial branching complexity and correlate it to microglia functional state during development, adulthood and degeneration, across sex, brain regions, and different disease progression states.

2. Anesthetic drugs such as isoflurane or KXA (ketamine-xylazine-acepromazine) either increase neuronal inhibition or block excitation to depress nerve-cell function, respectively, however their effect on glial cells is not well understood. We found that KXA triggers microglia to remove the perineuronal net, an extracellular matrix structure that is critical for plasticity. We could reveal that KXA treatment reopens the plasticity window.
Our study of ketamine’s effect on microglia function provides major novel insight, which will have immediate and far-reaching implications for the fields of neuroscience, immunology, human and veterinary medicine, as well as society.

Our study of ketamine’s effect provides a significant advance in the understanding of ketamine as a drug and yields new insights into possible therapeutic interventions. By removing the perineuronal net, we create a window of opportunity to reset wrongly wired neuronal connections that may cause neuropsychiatric symptoms.