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.
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.
