Microglia contribute to circuit defects in Mecp2 null mice independent of microglia-specific loss of Mecp2 expression

摘要

Rett Syndrome is a neurodevelopmental disorder with symptoms that typically begin in girls between 6 and 18 months old. Those affected developmentally stagnate and regress – during which they lose some of their previously acquired skills and develop an array of physical impairments. Mutations in a gene called Mecp2 on the X chromosome cause most cases of Rett Syndrome. Mice that lack the Mecp2 gene develop symptoms similar to those seen in people with Rett Syndrome, and so such “Mecp2 null” mice are often used to study the disorder. Microglia, the resident immune cells of the central nervous system, have been implicated in the development of Rett Syndrome. Introducing microglia that carry the Mecp2 gene into Mecp2 null mice has been shown to reduce several disease-associated abnormalities. However, exactly how microglia contribute to these changes remains unknown. In addition, a more recent report failed to reproduce these findings, and instead obtained results suggesting that microglia do not affect the development of Rett syndrome. Schafer et al. now use the mouse visual system as a model to determine if and how microglia contribute to the development of Rett Syndrome. Like many other brain regions, the developing visual system initially has a surplus of connections between neurons, or synapses, which are subsequently pruned back. Schafer et al. previously showed in the developing visual system of early postnatal (5 days after birth) control mice (who express the Mecp2 gene) that microglia contribute to this pruning by engulfing and eliminating a subset of these excessive synaptic connections. The new experiments by Schafer et al. show that another wave of microglia-mediated synaptic pruning occurs in 40-day-old juvenile control mice. Because Mecp2 null mice begin to display features of Rett Syndrome when they’re about 40 days old, Schafer et al. tested whether the microglia of these animals inappropriately prune synaptic connections. While this process occurred normally in neonatal and juvenile Mecp2 null mice, microglia began to excessively engulf cells in Mecp2 null mice when they were around 56 days old. Unexpectedly, deleting or reintroducing the Mecp2 gene solely in the microglia of these mice had little effect on pruning activity of the microglia, and failed to affect Rett-syndrome-like symptoms in the mice. Taken together, the data presented by Schafer et al. suggest how microglia contribute to the final stages of Rett Syndrome by dismantling circuits of neurons that are rendered vulnerable by the loss of the Mecp2 gene in other cell types.