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.

Public Health Relevance

Synapses in the visual system undergo constant remodeling not only during developmental stages but also during adult stages. However, how synapses are eliminated is still not well understood. In my preliminary study, I found that astrocytes actively engulf synapses in the visual system in a neural-activity dependent manner. This novel finding opens up exciting new possibilities in understanding several key questions in neurobiology: Astrocyte-mediated synapse elimination could be a fundamental link in explaining neural activity driven synapse elimination and synaptic plasticity. The results in this proposal would address whether the synaptic architecture of our brains is constantly being remodeled by astrocytes in response to our experiences and would have profound implications for our understanding of many neurobiological processes from visual system plasticity to learning and memory and for disease as wells.

Agency
National Institute of Health (NIH)
Type
Career Transition Award (K99)
Project #
1K99EY024690-01
Application #
8767269
Study Section
Special Emphasis Panel (ZEY1)
Program Officer
Agarwal, Neeraj
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Stanford University
Department
Biology
Type
Schools of Medicine
DUNS #
City
Stanford
State
CA
Country
United States
Zip Code
94304