Neural Engineers at Work
In a groundbreaking discovery, a new study published in the prestigious journal Cell reveals that a specific subset of microglia, the brain's resident immune cells, play a crucial role in maintaining the delicate balance of synapses in the brain. The study, co-authored by a team of researchers from Harvard Medical School and the Broad Institute of MIT and Harvard, among others, sheds light on the versatile roles microglia can play in wiring the brain. These roles include building neural connections and pruning them to remove synapses that are no longer needed. The research, which can be accessed at this link after the embargo lift, offers insights that could pave the way for treatments correcting underlying deficiencies in synaptic wiring. The study used a new imaging technology called MERFISH to visualize and differentiate between microglial cell subtypes in animals. The team discovered that some microglia are finely attuned to detecting and engaging exclusively with inhibitory synapses, the junctions that slow down the flow of information from cell to cell. These cells were named "inhibitory synapse-associated microglia" or "specialized microglia targeting inhibitory synapses". The contact between these cells and inhibitory synapses occurs via a GABA receptor that resides on the surface of microglia. GABA, the brain's main inhibitory neurotransmitter, appears to act as a come-hither signal to these cells, inviting them to feast on inhibitory, GABA-releasing synapses. In adulthood, the overabundance of inhibitory synapses in young animals turned into a deficiency. Removing GABA receptors from microglia cells in young animals led to behavioral changes, including disinterest, less physical activity, and less exploration. Conversely, matured animals lacking GABA receptors on their microglia became increasingly hyperactive, running and jumping more, and venturing to explore their environment more frequently. This finding suggests an over-compensatory mechanism at play in the matured animals. The insights from the study set the stage for new therapeutic approaches for conditions in which the brain's neural wiring goes awry. The work was supported by the National Institutes of Health, EMBO, Hearst Fellowships, Simons Foundation Autism Research Initiative, Harvard’s Dean Initiative, National Institute of Mental Health, a Broad Institute-Israel Science Foundation research grant, and National Institute of Neurological Disorders and Stroke. The brain's neural network is made up of billions of synapses, specialized junctions that regulate signal transmission between and across cells. Some synapses inhibit signal transmission, others accelerate it, maintaining a delicate balance in the brain. Co-author Beth Stevens serves on the scientific advisory board and is a minor shareholder of Annexon. Gordon Fishell is a founder of Regel. The journal for this study is Cell.
