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The role of NG2 cells in the neural network in health and disease

Periodic Reporting for period 2 - NG2-cells (The role of NG2 cells in the neural network in health and disease)

Reporting period: 2021-06-01 to 2022-05-31

In the brain, not only neurons contribute to forming the neuronal network, instead glial cells are as well important to support brain functions. Oligodendroglial cells generate myelin sheaths in order to support and protect neuronal fibers (or axons). We know that neurons die during the course of neurodegenerative diseases, such as Alzheimer’s and Parkinson’s Disease or Epilepsy. Neurodegeneration also affects the glial cells that are in contact with these neurons, as has recently been brought to the attention of researchers around the globe by genetic screens for risk factors. On the contrary, oligodendrocytes are lost during the course of the autoimmune disease Multiple Sclerosis, leaving the neurons at a high risk to degenerate. Based on demographic changes in Europe, it is expected that the number of patients suffering from neurodegenerative disorders will greatly increase in the decades to come. Thus, we urgently need more therapies that protect neurons and glial cells from degenerating.
In this project, we focus on oligodendrocyte precursor cells (OPCs or NG2 cells), that give rise to mature oligodendrocytes, the myelin generating cells of the central nervous system.
In contrast to neurons, which cannot be regenerated once they are lost (with very few exceptions), NG2 cells keep the ability to divide and generate new oligodendrocytes throughout life. Thus, NG2 cells could provide a great regenerative potential, if we understand how they are regulated, and if we find ways to positively influence their generation and maturation into oligodendrocytes. We study how NG2 cells react to alterations in neuronal activity in in vivo-models for epilepsy. In these models, mutations in ion channels that have been identified in human epilepsy patients are expressed in experimental systems, resulting in an increase in neuronal activity. Understanding the physiological and morphological interactions between neurons and NG2 cells in the healthy as well as in the diseased brain will help us to understand how they influence each other, and find possible points of intervention in order to enhance the capability of NG2 cells to regenerate oligodendrocytes that have been lost and protect neurons from degeneration.
During the preparation phase, brain tissue samples were collected from an in vivo-model of epilepsy and various protocols for light and electron microscopic analysis were applied in order to find the most suitable protocol. The number of NG2 cells in different regions of the brain under normal conditions as well as under conditions with increased neuronal activity was assessed. This was the starting point for the analysis performed during the outgoing phase at the University of Connecticut.
During the outgoing phase, a detailed analysis of interactions between NG2 cells and neurons was performed (see B in attached scheme). SpecificallySpecifically, we were interested to find out with which part of the neuron the NG2 cells will interact. Different levels of resolution were applied to assess not only the numbers of NG2 cells with lower resolutions, but moreover to be able to follow their processes with high resolution laser scanning confocal microscopy and different labelinglabelling techniques to generate a complete view of their interactions. Furthermore, we had the great opportunity to compare different models of increased neuronal activity, adding significant relevance to our findings. We also realized that NG2 cells frequently contact blood vessels in the brain (see C in attached scheme), where they could possibly play a role in ‘neurovascular coupling’, a recent concept describing how e.g. astrocytes that are localized at the blood vessels contribute to linking neuronal activity with blood flow and thus providing metabolic support to active brain regions (see A in attached scheme).
In addition, we got the chance to match our morphological findings to genetic data sets (obtained by RNA sequencing) from the same models that were generated at the University of Connecticut. The combination of these techniques enabled us to find putative target molecules of NG2 cells, shedding light on the mechanisms. These data are currently being prepared for publication.
During the return phase, we addressed the physiological changes in NG2 cells as a response to mutations that have been found in epilepsy. These results were the perfect addition to our morphological data generated during the outgoing phase, and can now be expanded to other models.
Neurological and mental disorders add an increasing burden on societies. Worldwide, they have become the leading cause of disability-adjusted life years (DALYs) and they are the second leading cause of death. In Europe’s ageing population, their impact is estimated to increase even more over the next decades.

Neuroscience recently moved away from solely studying neurons as a cause for dysfunction within the neural network. Instead researchers begin to study all cells in the central nervous system and are just starting to understand the contribution of non-neuronal cells to proper brain function.In line with this view, the goal of this project is to add more information on the role of glial cells, especially oligodendroglial cells, within the neural network and their interactions with neurons. Ultimately, we aim to understand how glial cells adjust their physiology once neuronal function is impaired. Understanding the interplay between different cell types in the brain will on the long-term lead to the discovery of new approaches for therapies that aim at improving or restoring neural network function in neurological disorders. In order to find the putative mechanisms and targets for new therapies, basic research is highly needed and will contribute to reduce the burden generated by neurological disorders.

We were able to describe novel contact points between neurons and NG2 cells in specific brain areas, which we are about to expand to other models. Unexpectedly, we found a high level of contact formation between NG2 cells and blood vessels, whose functional consequences still need to be explored. During the return phase, we will further added in vivo data to these settings. The expectedOur findings will contribute to understanding the regulatory mechanisms between NG2 cells and neurons and the role of NG2 cells within the neural network, and hopefully lead to the generation of new therapies that aim at restoring oligodendrocytes and myelin in neurodegenerative diseases where they have been lost. Thus, knowing the changes and stimuli causing changes in NG2 cell behaviour is a first step towards identifying new points of intervention for future therapies.
Scheme of interactions between OPCs, blood vessels, and active neurons