Following greater than seven years of research, researchers on the University of Seville-IBiS (Institute of Biomedicine of Seville) have identified a recent key cell type with a critical role within the developmental processes of memory and learning. This breakthrough has been published in the celebrated journal Nature Neuroscience.

The research, led jointly by the University of Seville-IBiS and Karolinska Institutet, helps to know how neural systems with decisive functions for human behavior mature. The in-depth study highlights the role of microglia, a bunch of cells that has been the topic of considerable information in recent times on account of its involvement in various brain pathologies similar to Alzheimer’s disease.

Microglia and their role in brain development

A bunch of immune cells present in the central nervous system (CNS) is often called microglia. These cells act because the CNS’s first line of defense against injury, infection and other threats. In addition they play a significant role in maintaining neuronal homeostasis, eliminating waste and remodeling synapses (the connections between neurons).

Microglia have historically been defined because the macrophages of the brain, and as such belong to the innate immune system. Nevertheless, it’s a really dynamic cell and it’s becoming increasingly clear that this group also plays a decisive role in very necessary functions of the central nervous system: in brain connectivity, in neurogenesis regulation [the appearance of new neurons], in neuronal excitability regulation, etc.”.

José Luis Venero, Professor of Biochemistry and Molecular Biology on the University of Seville and Head Researcher of the Neuronal Ageing Group at IBiS

Throughout the development of the central nervous system, within the early embryonic and early postnatal stages, quite a few neural systems are connected. That is what makes up the CNS. Microglia play a key role on this process. Potential alterations during these phases are related to neurodevelopmental diseases similar to autism spectrum disorders, bipolar disorders and various cognitive problems.

Discovering ARG1+ microglia

On this study the international research team led by the Institute of Environmental Medicine at Karolinska University in Sweden and the University of Seville in Spain have described how a specific subset of microglia express the enzyme Arginase-1. For that reason, the group of cells has been named ARG1+ microglia. Based on the study, it contributes to the establishment of the neuronal cholinergic system, which is involved in lots of necessary functions of the brain, during early postnatal development of mice.

Using whole-brain imaging of those animals, it was found that ARG1+ microglia are present in specific regions of the developing brain, predominantly within the basal forebrain and ventral striatum, where cholinergic neuron bodies are present in large numbers. The ARG1+ microglial subclass co-exists with the known homeostatic microglia (ARG1 -) inside these brain regions, indicating that they will need to have intrinsic properties. Sequencing evaluation of their genome showed that ARG1+ microglia exhibit a definite gene expression profile in comparison with microglia that don’t express ARG1.
“Our study has identified a selected subpopulation of microglia within the maturation of the cholinergic system,” said Professor Venero.

“It’s strongly affected when affected by Alzheimer’s disease. In reality, a lot of the newly identified risk genes for Alzheimer’s disease are very precisely related to microglia.” Because the professor points out, this relationship could reveal a correlation between ARG1+ microglia and the onset of diseases similar to Alzheimer’s disease.

“It stays to be seen whether the microglial population identified in our study has a direct relationship with this disease,” says Venero. “Nevertheless, it is vital to notice that Alzheimer’s disease has a better incidence in women. Interestingly, our study shows that the selective elimination of the gene that characterizes this subpopulation [identified as arginase-1] in microglia produces deficiencies in long-term memory processes, especially in female mice,” explained Rocío Ruiz, a member of the research team and senior lecturer within the Department of Biochemistry and Molecular Biology on the University of Seville.

The study offers a greater understanding of brain development and the contribution of microglial diversity to that process, and can also provide recent clues on find out how to manage neurodevelopmental or neurodegenerative disorders which have a cognitive component. “It should be taken into consideration that our study provides very relevant insights to know how neuronal systems with decisive functions in our behavior mature,” stated the expert.

From accidental discovery to the long run fight against Alzheimer’s disease

This research is the fruit of seven years of labor and represents, within the words of the researcher, “an infinite collective effort during which different national and international groups have participated.”
The study was co-led by Dr. Bertrand Joseph, from the Karolinska Institute in Sweden, and Dr. José Luis Venero, from the Institute of Biomedicine of Seville (IBiS), with the national collaboration of two groups from the Pablo de Olavide University (UPO) led by Dr. Jose ángel Armengol and Dr. Antonio Rodríguez-Moreno.

“The best challenge was identifying and characterizing the function of a recent microglial subpopulation,” says Professor Venero again. “The initial identification of this subpopulation was completely accidental. A post-doctoral student in Bertrand Joseph’s group, Vassilis Stratoulias, got down to test a battery of antibodies on brain tissue from young mice, finding selective labeling in areas related to cholinergic tissue. From then on, working together to attempt to characterize its function resulted within the selective deletion [elimination] of the ARG1 gene in microglia cells.

Further research, combining transcriptomics, cellular and molecular biology, behavioral, electron microscopy and electrophysiology techniques over the past seven years has led the group to discover and understand how the ARG1+ microglial population is involved within the maturation and establishment of long-term memory and learning processes.

“Our study reinforces a typical view that there are different microglial subpopulations with distinct functions inside the CNS. Microglial heterogeneity is very relevant throughout the stages of brain development. Incorrect microglial function will be the trigger within the etiopathology of major neurodevelopmental and even neurodegenerative diseases, similar to Alzheimer’s or Parkinson’s. This research helps to open up recent avenues to higher understand how they occur and the way we will combat them,” say experts. This research helps to open up recent avenues that can allow us to higher understand how they occur and the way we will combat them,” say the experts.

Source:

Journal reference:

Stratoulias, V., et al. (2023). ARG1-expressing microglia show a definite molecular signature and modulate postnatal development and performance of the mouse brain. Nature Neuroscience. doi.org/10.1038/s41593-023-01326-3.