- Awarded: 2012
- Award Type: Research
- Award #: 240394
Neurons are resident cells of our nervous system that are connected to one another through a structure called the synapse. These synaptic connections form the basis of nervous system function. Early in development, synapses form in excess and a subset must be eliminated during a process of synaptic remodeling to achieve the precise wiring diagram characteristic of the mature nervous system. If this process is disrupted, aberrant synaptic connections may lead to severe disruptions in behavior and overall function of the organism.
Abnormal synaptic connections have been observed in people with neurodevelopmental disorders, including autism. In addition to abnormal synapses, the brains of individuals with autism also exhibit abnormal microglia, the resident immune cells of our central nervous system (CNS). However, it remains unclear how microglia could be involved in the disorder.
Beth Stevens and her group’s previously published work demonstrated that microglia mediate the elimination of excess synapses in the developing brain by eating, or engulfing, synapses that are less active or ‘weaker1, 2.’ Stevens and her colleagues at Children’s Hospital Boston aimed to understand how microglia are involved in the pathogenesis of autism. They hypothesized that microglia-mediated engulfment of synapses is altered. They focused on two mouse models of autism: MeCP2 knockout, a genetic model of Rett syndrome, and Maternal Immune Activation (MIA), an environmental model of autism that induces inflammation during early embryonic development.
Their work identified that in these mice, as in people with autism, synapses and microglia are indeed abnormal. In the MeCP2 knockout mouse brains, synapses appear quite normal until late juvenile ages, when there is a significant reduction in synapse density. Moroever, in MeCP2 knockouts the researchers observe a concomitant increase in engulfment of synapses in the late juvenile brain, which is consistent with a decrease in synapse number over time.
Ongoing experiments are assessing similar microglia-synapse interactions in the MIA model and in mice in which MeCP2 gene expression is specifically disrupted in microglia. Results from these experiments may shed new light on mechanisms of disease and highlight an important role for microglia in synapse development.