The sequence-specific mRNA-binding protein CPEB1 (Cytoplasmic polyadenylation element-binding protein 1) regulates mRNA polyadenylation and translation and has been linked to defects in synaptic plasticity, learning, and memory. Synaptic connections between neurons are an essential determinant of cognitive function and are continuously surveyed by microglia, the glial cells of the brain with immunological function. Microglia affect the synapse number, and their activation correlates with synaptic pruning in many neurological disorders including aging. Our preliminary study shows that microglia purified from CPEB1-deficient mouse brain are activated and engulf an increased number of labeled synaptosomes as compared to WT. Using CPEB1 knockout mice, we find a significant reduction in synapse number in hippocampal region CA1. One key question to address is whether the synaptic loss we observe is microglia-autonomous or is due to CPEB1-deficiency in other cells such as neurons or other glia. To answer this question, we will create microglia-specific CPEB1 knockout (KO) animals. This proposal aims directly build on and expand our preliminary findings. Precisely, we will 1) Analyze loss of excitatory and inhibitory synapses in different brain regions during development, 2) Determine the involvement of CPEB1 in barrel cortex synapse elimination by microglia, 3) Generate microglia-specific CPEB1 KO animals, and 4) Determine the phagocytic ability of microglia in different brain regions during development.

Public Health Relevance

The current proposal seeks to understand the involvement of microglia in synaptic loss mediated by mRNA binding protein CPEB1. The proposed research is relevant to public health because reduced synapse number and increased microglial activity are important for mental health, neurological and neurogenerative disorders and aging.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Small Research Grants (R03)
Project #
1R03MH121871-01
Application #
9876820
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Tonelli, Leonardo H
Project Start
2019-12-02
Project End
2021-11-30
Budget Start
2019-12-02
Budget End
2020-11-30
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655