Grant: Project Grant

The developmental refinement of neural circuits involves an initial overproduction of synapses followed by a developmental pruning of inappropriate connections. Neural activity directs much of this refinement process. Microglia, the resident immune cells of the brain, are implicated in synaptic pruning, both through signaling and by nibbling excess synapses, a process called "trogocytosis". Genetic and histological evidence suggests an important role for microglia in neurodevelopmental disorders. Disruption of microglial and immune system signaling results in inadequate synapse elimination in some brain circuits. Such miswiring is believed to underlie neurodevelopmental disorders like autism spectrum disorder and schizophrenia. However, much of what we know comes from genetic correlation rather than direct observations of microglia acting on neurons in the developing brain. Our lab uses transparent albino tadpoles to perform in vivo time-lapse imaging of the developing visual system. This model allows repeated imaging of single cells and entire circuits in the intact animal over days. We can thus directly observe neuron-microglia interactions, including synaptic nibbling by microglia, as neurons fine-tune their connectivity, as well as perform manipulations that alter signaling by microglia or eliminate them entirely. We propose to use this model to directly observe the participation of microglia in the process of activity-dependent developmental circuit refinement. This will offer an unprecedented understanding of these fascinating cells and how they contribute to both healthy and abnormal brain development.