Microglia, the resident phagocytes of the central nervous system, play a crucial role in synapse elimination during circuit refinement. Synaptic connections initially made in excess are selectively removed by microglia in a neural-activity-dependent manner. Failure to appropriately refine synaptic connections is thought to be a key contributor to neurodevelopmental disorders such as intellectual disability and autism. Although synapse elimination is vital for proper circuit assembly, the molecular cues that microglia utilize to differentiate between synapses are not well understood. In the peripheral immune system, a balance between pro-phagocytic and anti-phagocytic signals enables discriminate phagocytosis. The pro-phagocytic cues that regulate how peripheral immune phagocytes clear their targets also regulate how microglia interact with neurons. However, the anti-phagocytic signals found in the peripheral immune system have not yet been identified in microglia. I will test if CD47-SIRP?, an anti-phagocytic signaling cascade described in the peripheral immune system, is required in the central nervous system to prevent inappropriate synapse removal. I hypothesize CD47-SIRP? signaling ensures appropriate circuit refinement in the developing postnatal brain by protecting select synapses against microglial phagocytosis. This study will be the first to reveal how anti-phagocytic signals mediate select synapse removal, a formative step in brain development.!

Public Health Relevance

The developing brain forms a surplus of neural connections (synapses), which are subsequently pared by microglia that engulf unwanted synapses. Inappropriate synapse removal is a leading contributor to neurodevelopmental disorders such as intellectual disability, schizophrenia, and autism. The goal of this research is to better understand how excess synapses are accurately removed by studying how microglia differentiate between synapses that should and should not be engulfed.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32NS098598-03
Application #
9696426
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Morris, Jill A
Project Start
2017-04-01
Project End
2020-03-31
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Boston Children's Hospital
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115