During the early stages of central nervous system development, neural systems interconnect, forming the foundation of the CNS. Microglia play a vital role in this process, and disruptions during these phases have been linked to neurodevelopmental disorders such as autism spectrum disorders, bipolar disorders, and cognitive problems.
The researchers discovered a particular subset of microglia that express the enzyme Arginase-1 (ARG1), leading to their classification as ARG1+ microglia. These cells were found to contribute to the development of the neuronal cholinergic system, which plays a key role in various brain functions, during the early postnatal development of mice. Whole-brain imaging revealed that ARG1+ microglia are concentrated in specific regions of the developing brain, particularly in the basal forebrain and ventral striatum, where cholinergic neurons are abundant. This discovery suggests that ARG1+ microglia possess distinct properties compared to other microglia.
The genome sequencing of ARG1+ microglia revealed a unique gene expression profile, emphasising their specific role in the maturation of the cholinergic system. Alzheimer's disease, which affects this system, is known to be associated with microglia. While the direct relationship between ARG1+ microglia and Alzheimer's disease remains to be determined, the researchers noted that the selective elimination of the gene characterizing this microglial subpopulation led to deficiencies in long-term memory processes, particularly in female mice.
This groundbreaking research was the result of seven years of collaboration between international teams, including the Institute of Environmental Medicine at Karolinska University in Sweden and the University of Seville in Spain, along with national groups from the Pablo de Olavide University. The study underscores the concept of microglial heterogeneity within the central nervous system, particularly during brain development. Malfunctioning microglia may play a pivotal role in the pathogenesis of major neurodevelopmental and neurodegenerative diseases like Alzheimer's and Parkinson's. By uncovering these microglial nuances, this research opens up new avenues for understanding the origins of these conditions and potential therapeutic interventions.