Brain development is a lengthy process that requires multiple interactions between the neurons and the immune cells, which starts from pregnancy and continues well after birth: a dialog that Sonia Garel has been successfully decoding for over 15 years.
Good brain function at birth and throughout life depends on the quality of its development starting from the very first weeks of gestation. However, "the assembly of the billions of neurons during pregnancy requires a complex choreography that involves multiple cells, explains Sonia Garel*, from the Institute of Biology of Ecole Normale Supérieure (IBENS) in Paris. That is why my team and I have chosen to take a broader view. We see the developing brain as a self-assembling structure for which we study all the players present at any given time: the neurons themselves of course, but also the glial cells that surround them, including the immune system microglia." Thanks to this singular approach, the team has been responsible for major advances, which have earned Garel the NRJ Foundation - Institut de France 2020 Grand Prize which, she is keen to stress, "pays tribute to the work of a great team and that of the many collaborations established over the years. Science isn’t something we do all by ourselves!"
From plant biology to neurobiology
While the neurobiologist is now internationally renowned, it was almost by chance that she came across the neurosciences. "In the beginning, I was interested in ecology and plant biology, which was why I joined AgroParisTech, she says. But as part of my curriculum, I studied a model of artificial vision." And with vision goes neurons. "It was then that I developed a passion for neurobiology and so I asked if exceptionally I could validate a Master’s in Cellular and Molecular Neurobiology in addition to my Engineering Diploma in Agronomy," she continues. From that point on, the developing brain has been a source of endless fascination for her. In 1994, she joined Patrick Charnay’s laboratory at the prestigious École Normale Supérieure (ENS) to do her dissertation. "This was where I identified genes involved in the differentiation of certain cells into neurons," she says. Then, for her postdoctoral fellowship, Garel chose to join John Rubenstein’s child psychiatry research laboratory at the University of California in San Francisco, "because it practiced an integrated approach, she clarifies. After working on the single neuron, I wanted to understand how populations of neurons assemble and connect, how they find their place in the developing brain." She then turned her focus to the formation of the different regions of the cerebral cortex. "I discovered that there is an initial template enabling the regions to pre-form. The information favoring each of them to specialize comes later," describes the researcher. Her findings were the subject of many publications. "The laboratory environment was effervescent but I continued to remain very European, she recognizes. I wanted to return to the Old Continent".
Back in Europe she obtained a Research Officer role at Inserm and rejoined her old laboratory at ENS in 2003. "I was very, very lucky because with Franck Bielle, who was a student back then, I was able to focus on the cerebral cortex while the team worked on the posterior cortex," she emphasizes. She established that during development neurons migrate and establish temporary bridges that guide the axons towards the cortex. "In other words, the brain is a machine that forms in small steps – ‘tweaks’ based on interactions between cells that do not necessarily continue to remain connected. This research, which Ludmilla Lokmane is continuing in my current team, is highly fundamental. But it helps to identify wiring defects responsible for neurodevelopmental conditions such as autism disorders and schizophrenia."
The role of the microglia
In order to continue in that direction, in 2008 the researcher created her own Inserm team, still at ENS. "We looked at all the cells potentially implicated in brain development, particularly the microglia, she adds. These immune system cells protect the brain from lesions and infections, colonizing the brain at a very early stage when the first neurons are forming. We supposed that they could participate in its development, and so we studied their role." A hypothesis that the team, particularly Morgane Thion, has confirmed several times over by identifying various roles played by the microglia, some of which unexpected. "In collaboration with Étienne Audinat and Isabelle Ferezou at the Paris-Saclay Institute of Neurosciences, we saw that the microglia participate in the construction of certain major inhibitory circuits, and which intervene particularly in the control and organization processes we use daily, describes the researcher. Also, with Florent Ginhoux from the Singapore Immunology Network, we established that the microglia are sensitive to the gut microbiota, a phenomenon that differs according to sex. Faced with disruption during gestation, they are particularly affected in males. But if the disruption occurs in adulthood, it is in females that the microglia are the most destabilized. Astonishingly, this sexual dimorphism echoes that seen in the disorders associated with microglial dysfunction: the neurodevelopmental disorders that mainly affect boys, and the Alzheimer-type neurodegeneration that mainly affects women."
Next on the agenda for the team is to study how the microglia acquire different functions, "a phenomenon we think is due to the dialog they establish with the surrounding neurons." These interactions are so important that a Chair of Neurobiology and Immunity has recently been created at Collège de France. Sonia Garel has been its professor since early autumn 2020, which has delighted her almost as much as her research. "I enjoy training young scientists and passing on knowledge, which is what I already used to do at ENS. Joining Collège de France is a wonderful mission, she declares. In addition, I’ve been lucky enough to have both a career and a family life, a situation I can see is sometimes difficult for young women today. So in 2019 I started to get involved in supporting women in science." Her objective: for increasing numbers of young female researchers to enjoy the scientific opportunities that she had.
1994. Master’s in Cellular and Molecular Neurobiology and Engineering Diploma in Agronomy
1999. Ph.D. in Cellular Neurobiology
2003. Inserm Research Officer
2008. Creation of her own Inserm team
2010-2017. Associate Professor at the École Polytechnique
2020. Neurobiology and Immunity Chair Professor at Collège de France
*unit 1024 Inserm/CNRS/ENS, Brain Development and Plasticity team