Role of microglia and strategies of neuroprotection in neonatal brain damage

As brain-resident immune cells, microglia have the ability to sense the brain environment and adapt functions to maintain homeostasis. Microglia is also critically involved in neurodevelopmental processes required for proper brain maturation and function. Any perpetuation of these brain-building roles by early exposure to any environmental stress could explain long-term consequences on neurological abilities seen in neurodevelopmental diseases (ND) associated to prematurity or neonatal traumatic brain injuries (TBI).

In a mouse model of encephalopathy of prematurity (Eop) induced by early exposure to inflammation we recently demonstrated that microglial have regional-specific pattern of reactivity and drive hypomyelination, the main feature of Eop (Klein L. et al., Glia 2022 ; Van Steenwinckel J. et al., Brain 2019). We implemented a specific study within Eop’s mouse hippocampi that supported the onset of specific pro-inflammatory processes inducing a decrease in the proliferation of the Tbr2+ intermediate progenitors and later persistent hippocampal dependent behaviors including increased signs of anxiety and long-term spatial memory deficits (Veerasammy S. et al., Brain Behav Immun Health 2020).

Using large-scale analysis of microglia transcriptomic modifications, we identified original and promising molecular systems to modulate microglial reactivity including Dlg4 encoding the post-synaptic density 95 protein (Krishnan M.L. et al., Nat Commun 2017), the WNT pathway (Van Steenwinckel J. et al, Brain 2019) and the immunomodulatory microRNA 146b-5p (Bokobza C. et al., Ann Neurol 2022).

We demonstrated that DLG4 protein is synthesized by microglia in immature mouse and human brain and developmentally regulated. Dlg4 could play a critical role in microglia reactivity as a hub protein. Genetic variation in DLG4 impacts inter-individual susceptibility to injury after preterm birth.

Using nanoparticle-based drug delivery therapy, we specially activated the WNT pathway and overexpressed the microRNA 146-5p in microglia and improving developmental trajectories of EoP mice including myelination and memory and social abilities.

Neonatal TBI induced by weight drop trauma have also demonstrated neuroinflammation processes characterized pro-regenerative and immunoregulatory microglial reactivity (Chhor V. et al., Brain Behav Immunol 2017) paving the way for an in-depth analysis of the molecular pathways driving reactivity for therapy design.

Disturbance of oligodendrocytes (OLs) maturation and myelination seem to be a common and major futures of developing brain exposed to early inflammatory events. We demonstrated that OL precursor cells and immature OLs have the capability to react to inflammation but also modulate immune reactivity of microglia. Specifically, we highlighted that immune and inflammatory pathways are developmentally downregulated along the OL maturation, and early inflammatory process in EoP mouse brain altered cell development and identity in maturing OLs (Schang AL. et al., Cell Death Dis 2022). In addition, we revealed a specific immune reactivity of OLs that play a critical role in shaping the microglia reactivity during inflammation (Boccazzi M. et al., Cell Death Dis 2021).