The role of microglia in activity-dependent neuronal network maturation and maintenance

Neurons comprise only less than half of the nervous system, yet some of all those other cells have been largely ignored. Microglia are the tissue resident macrophages of the brain. These cells play a key role in shaping neuronal network formation during development and subsequently help to maintain a stable and healthy brain. After birth our brain contains overabundant neuronal connections and some of these must be refined and eliminated. Microglia scavenge the unnecessary connections via synaptic pruning and shape the neuronal network. Any abnormality in this interaction during neuronal network formation and maintenance can lead to a variety of neurodevelopmental disorders such as autism or schizophrenia. Yet, neither the risk factors underlying these disorders nor the mechanisms that regulate synaptic pruning in the developing brain are well understood. My DPhil project tested the hypothesis that excitation or inhibition of specific neurons in a neuronal network changes microglial behaviour and dynamics leading to altered communication between microglia and neurons. Using a mouse model, I selectively removed parts of the Snap25 gene, and it produced a non-functioning protein in a subset of cortical layer 5 projection neurons and some hippocampal dentate gyrus neurons and thus also eradicated their ability to release synaptic vesicles in a regulated manner from around the time of birth in a chronic fashion. I observed that abolition of Snap25 expression reduced microglial activity and altered synaptic maturation. Also, it affected microglia-neuron communication by disrupting normal chemokine and phagocytic signalling. Lastly, I observed sex-specific changes in microglia-neuron communications, and this indicated that male mice were more sensitive to abolished Snap25-mediated release of synaptic vesicles during brain development. To test whether the same changes would apply for more acute silencing, I used chemogenetic manipulation to increase or reduce network activity of the same subpopulation of layer 5 and ...