Abstract
Microglia are the immune cells of the central nervous system that play important roles in brain pathologies. Microglia also help shape neuronal circuits during development, via phagocytosing weak synapses and regulating neurogenesis. Using in vivo multiphoton imaging of layer 2/3 pyramidal neurons in the developing somatosensory cortex, we demonstrate here that microglial contact with dendrites directly induces filopodia formation. This filopodia formation occurs only around postnatal day 8–10, a period of intense synaptogenesis and when microglia have an activated phenotype. Filopodia formation is preceded by contact-induced Ca2+ transients and actin accumulation. Inhibition of microglia by genetic ablation decreases subsequent spine density, functional excitatory synapses and reduces the relative connectivity from layer 4 neurons. Our data provide the direct demonstration of microglial-induced spine formation and provide further insights into immune system regulation of neuronal circuit development, with potential implications for developmental disorders of immune and brain dysfunction.
Highlights
Microglia are the immune cells of the central nervous system that play important roles in brain pathologies
We propose that filopodia formation by microglia promotes the maturation of specific neuronal circuit connections through the formation of functional mature synapses
To visualize microglia–dendrite interactions, we performed in utero electroporation of embryonic day (E)14–E15 ionized Ca2 þ binding adapter molecule 1 (Iba1)-EGFP mice with red fluorescent protein (RFP)
Summary
Microglia are the immune cells of the central nervous system that play important roles in brain pathologies. Using in vivo multiphoton imaging of layer 2/3 pyramidal neurons in the developing somatosensory cortex, we demonstrate here that microglial contact with dendrites directly induces filopodia formation This filopodia formation occurs only around postnatal day 8–10, a period of intense synaptogenesis and when microglia have an activated phenotype. Addition of microglial cells to hippocampal neuronal cultures could increase the number of dendritic spines via release of interleukin-10 (IL-10)[23], whereas the effect of estradiol to promote increased spine density in cultured pre-optic neurons depends on the presence and function of microglia[24] Release of cytokines such as IL-10 by microglia is typically associated with an activated microglia phenotype, such as occurs when microglia begin to populate the cortex during early postnatal development. We propose that filopodia formation by microglia promotes the maturation of specific neuronal circuit connections through the formation of functional mature synapses
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