Immune cells active in brain development
Microglia are cells that fight brain diseases and injury by swallowing foreign "objects" and activating repair molecules. Recent research suggests these cells are active even under normal conditions, and contribute to sculpting neural circuits.
Researchers at the National Institute for Physiological Sciences (NIPS) have uncovered new mechanisms microglia use to sculpt neural circuits. They found how microglia contact neurons to induce formation of new neural projections which then connect with other neurons increasing, and sometimes strengthening, brain connections.
This evidence could help explain how developmental disorders such as autism and schizophrenia might occur.
Early in development, neurons in the brain are highly active in seeking out and forming connections with other neurons. Microglial cells, first identified as protection in the brain against infection and destruction, recently are being seen to aid brain development.
Featured in Nature Communications, the research uses a combination of cell and molecule fluorescent labels, placed in developing mouse brains, to clarify how microglia affect formation of neuronal circuits.
They found that direct contact between microglia and dendrites (parts of neurons) enable them to communicate with each other.
This contact induces formation of filopodia — or the thin tendrils that project out from dendrites — to seek terminals of other neurons. These form synapses, enabling nerve communication.
"We were able to image microglia contacting dendrites - dendrite contact caused quite a rapid appearance and growth of filopodia" lead author Akiko Miyamoto says. "We found that such contact was associated with accumulation of Ca2+ and actin. Blocking microglia activity led to fewer synapses and less specific cortical circuits."
These findings could have important implications for a range of developmental diseases. Various studies have revealed associations between immune cells and neurodevelopmental disorders.
"We know that some brain disorders are linked to abnormal numbers of synapses or to changes in their shape and function.
"Disruption of the immune environment in the developing brain could be linked to disorders.
"Our new findings show how microglia create filopodia that go on to produce synapses - and could give us new targets for treating mental conditions."
Junichi Nabekura PhD, corresponding author.
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.
The article "Microglia contact induces synapse formation in developing somatosensory cortex" was published in Nature Communications at DOI: 10.1038/ncomms12540
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