Abstract
BACKGROUND: Microglia are brain-resident macrophages that play a crucial role in synapse pruning during the development and progression of various neuropsychiatric disorders, including autism spectrum disorder (ASD) and Alzheimer's disease (AD). Mechanistically, CD47 protein acts as a potent 'do not eat me' signal, protecting synapses from phagocytosis by microglia. However, the functional role of the upregulated neuronal CD47 signal under both physiological and pathological conditions remains unclear. RESULTS: We utilized an adeno-associated virus gene expression system to induce neuron-specific overexpression of CD47 in wild-type and 5xFAD mice, assessing its effects on microglial synaptic phagocytosis and mouse behaviors. Our results indicate that neuronal CD47 induces ASD-like behaviors and synaptic pruning defects, while promoting behavioral disinhibition and improving memory in wild-type mice. Single-nucleus RNA sequencing was employed to profile gene expression patterns in subpopulations of neurons and microglia. Notably, neuronal CD47 enhances synaptic pathways in neurons and particularly shifts microglial subpopulations from a disease-associated state to a homeostatic state. Additionally, neuronal CD47 reduces excessive microglial synaptic phagocytosis induced by Aβ pathology in 5xFAD mice. CONCLUSION: Our study provides evidence that neuronal CD47 overexpression results in synaptic pruning defects and is involved in the pathogenesis of ASD, while also playing a beneficial role in mitigating excessive synaptic loss in Alzheimer's disease.