Neuroscience. How many cell types does it take to wire a brain?

M icroglia, highly mobile immune cells that reside in the central nervous system, are traditionally viewed as “barometers” of the brain because they rapidly respond to cellular damage caused by injury and disease by engulfing and cleaning up debris ( 1). Imaging studies, however, have revealed that microglia are also ceaselessly active in healthy brains, and other studies have shown that this activity is often associated with synapses, which move signals between neurons ( 2– 4). Despite these intriguing observations, the function of microglia at healthy synapses has been elusive. On page 1456 of this issue, Paolicelli et al. ( 5) help pin it down. They demonstrate that micro glia are involved in the development of brain wiring in newborn mice and that disrupting micro gliasynapse interactions delays the maturation of synaptic circuits. The fi nding offers insight into the mechanisms underlying synapse maturation and into brain diseases in which synaptic connectivity is altered. In the brain, microglia are the only cells that express the fractalkine receptor CX3CR1; it specifi cally binds the chemokine fractalkine CX3CL1, which is expressed by neurons ( 6). Fractalkine signaling often modulates the activation of microglia response to injury or disease ( 7, 8). In genetically modifi ed knockout (KO) mice unable to produce the fractalkine receptor (Cx3cr1), there is a transient decrease in microglial density in several developing brain regions, including the hippocampus, a region critical for learning and memory. To determine whether this decrease affects the development of hippocampal synapses, the researchers compared Cx3cr1 mice with age-matched controls, looking for anatomical, electrophysiological, and behavioral abnormalities associated with disrupted synaptic maturation. They observed that newborn Cx3cr1 mice had an increased density of hippocampal spines, small protrusions from a neuron’s dendrite that receives synaptic input from presynaptic axons. This observation is consistent with a role for microglia in “pruning” of unneeded spines in normal mice during brain development. Indeed, the researchers observed postsynaptic-density (PSD) immunoreactivity within microglia cytoplasm, suggesting that microglia engulf and remove spines during this period of synaptic remodeling. In addition, electrophysiological and behavioral experiments demonstrated a delay in the maturation of hippocampal synapses in the KO mice. For example, elecHow Many Cell Types Does It Take to Wire a Brain? NEUROSCIENCE