Biology session

Neurodegenerative diseases impose an evergrowing burden for society, and therefore the research on the cellular and molecular background of brain-disease mechanisms is of paramount importance. Recently, it has been discovered that inflammatory processes are heavily involved in almost all neurodegenerative states, and the key roles of microglia in neuroinflammation has also been confirmed. Microglia are the primary immune cells of the central nervous system (CNS) and contribute to diverse physiological and pathophysiological processes. The previous work of our group proved that microglia have a protective role after acute brain injury and are able to regulate neuronal network activity. However, the main communication interface between microglia and neurons has not been identified yet. Thus, our main research aim is to decipher the functional anatomy of microglia-neuron interactions.

Until recently, resarch targeting the interactions between these two cell types focused almost exclusively on microglial contacts affecting the synaptic connections of neurons. Using multiple immunohistochemical labeling and confocal laser scanning microscopy we made a stunning discovery that microglia also establish connections with the cell bodies of neurons. Using immunogold labeling and transmission electron microscopy, we confirmed that this interaction site is a direct membrane contact which is characterized by the accumulation of microglia specific, purinergic P2Y12 receptors. Previous studies have already described that the main chemotactic stimulus for microglia is ATP and its derivatives. This prompted us to examine the location of mitochondria and vesicular nucleotide transporters, which are responsible for ATP production and release, respectively. We found that both mitochondria and vesicular nucleotide transporter proteins are enriched within neuronal cell bodies where microglial processes contact the somata. The neuronal accumulation of Kv2.1 protein has been described at membrane segments associated with intensive exo- and endocytosis. We conducted a density-analysis, and found that the Kv2.1 signal is much stronger on the surface of neurons where microglia connect the somata. This finding supports the idea that these connections are special communication hotspots for inter-cellular communication. Based on our results we conclude that the microglial processes establish distinct contacts on the somata of neurons which are characterized by the enrichment of proteins and cell organelles important in transcellular signal transmission.

The newly identified morpho-functional unit may be a privileged area of microglia-neuron interactions. Through this connection microglia is in an ideal position to directly monitor and regulate neurons. The detailed exploration of the relationships between microglia and neurons could open new perspectives for the defense against human brain diseases and help in the development of targeted therapeutic methods in the future.