Research led by the US and IBiS identifies a new cell type that is key in the development of memory and learning

The research, led jointly by the University of Seville-IBiS and Karolinska Institutet, helps to understand how neural systems with decisive functions for human behaviour mature. The in-depth study highlights the role of microglia, a group of cells that has been the subject of substantial information in recent years due to its involvement in various brain pathologies such as Alzheimer's disease.

Microglia and their role in brain development

A group of immune cells found in the central nervous system (CNS) is known as microglia. These cells act as the CNS's first line of defence against injury, infection and other threats. They also play a major role in maintaining neuronal homeostasis, eliminating waste and remodelling synapses (the connections between neurons).

"Microglia have historically been defined as the macrophages of the brain, and as such belong to the innate immune system," explained José Luis Venero, Professor of Biochemistry and Molecular Biology at the University of Seville and Head Researcher of the Neuronal Ageing Group at IBiS. "However, it is a very dynamic cell and it is becoming increasingly clear that this group also plays a decisive role in very important functions of the central nervous system: in brain connectivity, in neurogenesis regulation [the appearance of new neurons], in neuronal excitability regulation, etc.".

During the development of the central nervous system, in the early embryonic and early postnatal stages, numerous neural systems are connected. This is what makes up the CNS. Microglia play a key role in this process. Potential alterations during these phases are related to neurodevelopmental diseases such as autism spectrum disorders, bipolar disorders and various cognitive problems.

Discovering ARG1+ microglia

In 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 particular subset of microglia express the enzyme Arginase-1. For this reason, the group of cells has been named ARG1+ microglia. According to the study, it contributes to the establishment of the neuronal cholinergic system, which is involved in many important functions of the brain, during early postnatal development of mice.

Using whole-brain imaging of these animals, it was found that ARG1+ microglia are found in specific regions of the developing brain, predominantly in the basal forebrain and ventral striatum, where cholinergic neuron bodies are found in large numbers. The ARG1+ microglial subclass co-exists with the known homeostatic microglia (ARG1 -) within these brain regions, indicating that they must have intrinsic properties. Sequencing analysis of their genome showed that ARG1+ microglia exhibit a distinct gene expression profile compared to microglia that do not express ARG1.

"Our study has identified a specific subpopulation of microglia in the maturation of the cholinergic system," said Professor Venero.

"It is strongly affected when suffering from Alzheimer's disease. In fact, most of the newly identified risk genes for Alzheimer's disease are very precisely associated with microglia.” As the professor points out, this relationship could reveal a correlation between ARG1+ microglia and the onset of diseases such as Alzheimer's disease.

"It remains to be seen whether the microglial population identified in our study has a direct relationship with this disease," says Venero. "However, it is important to note that Alzheimer's disease has a higher incidence in women. Interestingly, our study shows that the selective elimination of the gene that characterises 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 in the Department of Biochemistry and Molecular Biology at the University of Seville.

The study offers a better understanding of brain development and the contribution of microglial diversity to that process, and may also provide new clues on how to manage neurodevelopmental or neurodegenerative disorders that have a cognitive component. “It must be taken into account that our study provides very relevant insights to understand how neuronal systems with decisive functions in our behaviour mature," stated the expert.

From accidental discovery to the future fight against Alzheimer's disease

This research is the fruit of seven years of work and represents, in the words of the researcher, "an enormous collective effort in 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 greatest challenge was identifying and characterising the function of a new 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, set out to test a battery of antibodies on brain tissue from young mice, finding selective labelling in areas associated with cholinergic tissue. From then on, working together to try to characterise its function resulted in the selective deletion [elimination] of the ARG1 gene in microglia cells.

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

“Our study reinforces a common view that there are different microglial subpopulations with distinct functions within the CNS. Microglial heterogeneity is especially relevant during the stages of brain development. Incorrect microglial function may be the trigger in the aetiopathology of major neurodevelopmental or even neurodegenerative diseases, such as Alzheimer's or Parkinson's. This research helps to open up new avenues to better understand how they occur and how we can combat them," say experts. This research helps to open up new avenues that will allow us to better understand how they occur and how we can combat them," say the experts.