Historically, it was thought that the brain lacked an immune system because the blood-brain barrier prevents the entry of immune cells from the rest of the body. However, we now know that the brain has its own resident immune cells known as microglia. While microglia are known to be involved in the brain’s response to infection and disease, in the last decade, work from many labs has suggested that they are also important in sculpting brain circuits during early development. These cells perform such functions as engulfing (or “eating”) weak synapses and promoting the maturation of stronger synapses. However, it is still unclear whether microglia continue to carry out these functions throughout adulthood or if their job is done after early development.
This question was tackled through a collaboration initiated by Jenelle Wallace, a joint graduate student in Beth Stevens’ lab (at Boston Children’s Hospital), which specializes in studying microglia, and Venkatesh Murthy’s lab here in MCB, that focuses on the mouse olfactory system. To ask whether microglia take an active role in plasticity in the adult brain, Wallace et al. looked in the olfactory bulb, where a form of neural development continues throughout adulthood. In mice, this brain region, which is the first area that processes the sense of smell, has the unique property of being able to incorporate new neurons throughout the animal’s life in a process known as adult neurogenesis (in contrast to most other brain regions, where all the neurons are formed during embryonic development). This remarkable process involves adult-born neurons migrating into the existing circuit and making new connections, possibly contributing to the ability to discriminate between novel odors in the environment.
To figure out whether microglia are important in this process, Wallace et al. imaged microglia in the olfactory bulb. Microglia have dozens of fine processes that constantly survey the brain environment on a timescale of minutes; Wallace et al. found that microglial processes consistently came close to synapses on the adult-born neurons more often than would be expected by chance. To find out whether this meant that the microglia were somehow regulating these synapses, Wallace et al. ablated microglia using a drug that specifically targets microglia and then measured the effects on the new neurons. They measured neuronal responses while mice sniffed fifteen different odors and found that the new neurons that developed without microglia responded to fewer odors. These neurons also had weaker excitatory synapses and smaller dendritic spines, suggesting that they had not been properly incorporated into the circuit. However, other features of the new neurons, including their migration to the olfactory bulb and changes in excitability over development were unaffected, suggesting that microglia specifically regulate synapse development and refinement in these neurons. Furthermore, neurons that were already mature before microglia were removed were relatively unaffected, suggesting that microglia target their functions to developing rather than mature neurons.
This work suggests that microglial regulation of adult-born neuron development could contribute to ongoing plasticity in the olfactory system. Future work is ongoing to understand which molecular pathways allow microglia to regulate synapse development in adult-born neurons and whether this mechanism is similar to what happens during early brain development. Elucidating how new neurons integrate into existing brain circuits (and the mechanisms and cell types, such as microglia, that regulate this process) helps clarify the limits of plasticity in the adult brain and could eventually open up the possibility of repairing aging or diseased brains.
by Jenelle Wallace and Venki Murthy
