Inserm, Université de Paris, Hôpital Robert Debré, Paris, France
Roles of microglia in NDDs
Epidemiological studies have shown a strong association between perinatal infection / inflammation and brain abnormalities in the preterm neonate and/or neurological/psychiatric deficits in survivors. Postmortem studies in preterm infants have revealed three hallmarks: microglial activation, oligodendrocyte maturation blockade, and deficits of specific subgroups of interneurons. Experimental studies have allowed to show a causal effect of infection / inflammation on perinatal brain development impairment, with a key role of microglia in this process. In this context, exposure of newborn mice to low doses of interleukin-1-beta during the neonatal period has been shown to disrupt oligodendrocyte maturation, myelin formation and interneuron equipment. These white matetr abnormalities are moderate during the developmental period but do persist until adulthood. They lead to permanent deficiencies in cognitive and behavioral tests without detectable effects on motor functions. The underlying molecular mechanisms include alterations of the transcription of genes implicated in oligodendrogenesis, myelin formation and axonal maturation. In this brain maldevelopment, microglia activation has been shown to be a key driver. Microglial activation during critical phases of brain development can result in short- and long-term consequences for neurological and psychiatric health. Several studies in humans and rodents have shown that microglial activation, leading to a transition from the homeostatic state toward a pro-inflammatory phenotype, has adverse effects on the developing brain and neurodevelopmental disorders. Targeting pro-inflammatory microglia may be an effective strategy for protecting the brain and attenuating neurodevelopmental disorders induced by inflammation. We will focus on the role of inflammation and the activation of immature microglia (pre-microglia) soon after birth in prematurity-associated neurodevelopmental disorders, and the specific features of pre-microglia during development. We will also highlight the relevance of immunomodulatory strategies for regulating activated microglia in a rodent model of perinatal brain injury. An original neuroprotective approach involving a nanoparticle-based therapy and targeting microglia, with the aim of improving myelination and protecting the developing brain, will also be addressed.
Altogether, these clinical and experimental data strongly support the hypothesis that exposure to infection / inflammation during pregnancy or the perinatal period is deleterious for the brain. This can lead to the appearance of perinatal brain maldevelopment that can lead to NDDs.
Pierre Gressens received his MD (UCL, Brussels, Belgium) in 1989 and his Ph.D. at UCL in 1995. He specialized in Child Neurology and carried out his post-doctoral research training at NIH (Bethesda, USA). He has been working at Robert Debré Hospital, Paris both as researcher and child neurologist since 1995. Currently, he is the Director of the INSERM–Université de Paris laboratory (U1141). Dr. Gressens’ laboratory has been involved with the basic and applied aspects of research in the area of neurodevelopmental disorders, with a focus on neuroinflammation. He has published more than 300 original papers.