The Influence of Changes in Microglia Development on the Plasticity of the Developing Visual Cortex Circuit in Juvenile Mice

Abstract

PURPOSE. To investigate the role of microglial subtypes in mouse visual cortex development, focusing on ocular dominance plasticity and interactions with GABAergic neurons and the extracellular matrix. METHODS. Immunofluorescence and single-nucleus RNA-sequencing (snRNA-seq) were used to study microglia in the binocular primary visual cortex (V1) from postnatal day (P) 11 to P42. Gene ontology (GO) analysis assessed synapse organization, and the impact of microglial disruption on ocular dominance plasticity was examined. Visual evoked potentials and miniature postsynaptic current recordings are used to monitor functional changes in V1. RESULTS. Microglia underwent a marked expansion between P11 and P21 and stabilized after P35, coinciding with notable changes in gene expression that aligned with synaptic remodeling. GO analysis at P14 and P28 revealed significant enrichment in synaptic organization linked to microglia. Single-nucleus RNA sequencing identified six distinct microglial clusters, among which two functionally relevant subpopulations were closely linked to cortical synaptic plasticity. One cluster, enriched in inflammatory responses and endocytosis, peaked at P21, whereas another cluster, associated with synapse organization and signaling, exhibited dynamic changes after eye opening and during the critical period, significantly influencing cortical synaptic plasticity. In parallel, perineuronal nets (PNNs) and PV(+) interneuron populations increased and reached steady levels by P42, suggesting that microglia help coordinate the timing of inhibitory circuit maturation. Disrupting microglial function during the critical period impaired ocular dominance plasticity, but this effect was reversed after treatment cessation. Mechanistically, microglial depletion enhanced PV(+) interneuron numbers, elevated PNN expression, and altered synapse development. CONCLUSIONS. Our findings highlight specific microglial subtypes as key regulators of cortical synapse development and plasticity through their interactions with PV(+) interneurons and PNNs. These insights advance our understanding of microglial contributions to visual cortex development and provide potential avenues for targeting microglial function to modulate cortical plasticity.