How does neuronal activity control the synaptic wiring of our visual system?

Stanford University, Stanford CA

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Abstract

DESCRIPTION (provided by applicant): To achieve precise neural connectivity, the developing mammalian nervous system undergoes extensive activity-dependent synapse remodeling. Recently microglial cells have been shown to be responsible for a portion of synaptic remodeling, but the remaining mechanisms remain mysterious. My preliminary work has found a novel role for astrocytes in actively engulfing CNS synapses. By phagocytizing synapses through the MEGF10 and MERTK phagocytic pathways, astrocytes actively contribute to the activity-dependent synapse pruning and elimination that mediate neural circuit refinement in the developing and adult mouse brain. Retinal ganglion cells (RGCs) in developing mice deficient in both Megf10 and Mertk pathways fail to normally refine their connections and retain excess functional synapses with neurons in their major diencephalic target, the dorsal lateral geniculate nucleus (dLGN). Importantly, blocking RGC activity in both eyes significantly reduced astrocyte-mediated phagocytosis of bilateral synaptic inputs whereas selective weakening only one eye induced preferential engulfment of the weaker (silenced) synapses. These findings demonstrate that astrocyte- mediated synapse elimination is a novel mechanism by which neural activity helps to sculpt the synaptic architecture of the brain and raise several questions. 1) How does neural activity control the rate of astrocyte-mediated synapse phagocytosis? 2) Does astrocyte-mediated synapse phagocytosis underlie visual experience dependent, critical period plasticity in the visual system such as ocular dominance plasticity? The long-term goal of this proposal is to elucidate the molecular mechanisms of activity-dependent synapse elimination by astrocytes and its physiological role in our brain, particularly focused on the visul system. In my proposed work I will take advantage of both in vitro and in vivo preparations, as well as optogenetic methods, to test the hypotheses that neuronal activity promotes synapse engulfment by astrocytes through increasing intracellular calcium levels in astrocytes, and that this process underlies ocular dominance plasticity.