Les macrophages (MΦ) du système nerveux central forment la microglie, qui contrôle son homéostasie. Plusieurs modèles de "fate mapping" ont montré que la microglie provenait du Sac vitellin (SV). Celui-ci produit les MΦ en deux vagues indépendantes. Dans la première, des progéniteurs restreints génèrent des MΦ primitifs, alors que dans la seconde, des progéniteurs érythro-myéloïdes produisent des MΦ définitifs. Les progéniteures primitifs et définitifs ont les mêmes phenotype et voie de différenciation. Leurs spécificités et leurs contributions aux étapes ultérieures du développement sont donc encore incomprises. Nous montrons que l'expression du facteur de transcription Lyl-1 discrimine les populations de MΦ primitifs et définitifs. Les MΦ primitifs Lyl-1+ fournissent la microglie de l'embryon. De plus, l'invalidation de Lyl-1 disruption conduit à une production accrue de MΦ primitive dans le SV précoce, puis à une réduction du contingent microglial à deux stades spécifiques du développement. Lyl-1 est spécifiquement exprimé par la microglie et aucun autre type cellulaire nerveux. Son inactivation conduit à des modifications comportementales typiques de l'anxiété sociale. Nous identifions donc Lyl-1 comme un marqueur des MΦ primitifs du SV qui donnent naissance à la microglie de l'embryon. Nous montrons également que Lyl-1 contrôle l'expansion et la différenciation de la microglie, et est ainsi impliqué dans la régulation des processus du neuro-développement. / Microglia are tissue macrophages (MΦ) of the central nervous system that control tissue homeostasis. Different fate mapping models have shown that microglia originates from the yolk sac (YS). Macrophages production in the YS occurs in two independent waves. In the first, primitive MΦ originate from restricted progenitors, while in the second, definitive MΦ are produced by erythro-myeloid progenitors. Because primitive and definitive MΦ progenitors share the same phenotype and differentiation pathway, their specific features and contribution to further developmental steps are still poorly understood. We here show that the expression of thee transcription factor Lyl-1 discriminates primitive and definitive MΦ populations. YS-derived Lyl-1+ primitive MΦ contribute to embryonic microglia. Moreover, Lyl-1 disruption results in an increased production of primitive MΦ progenitors in the early YS. It also leads to the reduction of the microglia pool at two specific development stages. Lyl-1 is specifically expressed in microglia, but not other brain cells and its inactivation leads to behavioral changes typical for social anxiety disorders. Thus, we identify Lyl-1 as a marker for YS primitive MΦ that will give rise to the entire microglia. We show that Lyl-1 controls microglia expansion and differentiation and is involved in the regulation of neurodevelopmental processes.

Die vorliegende Arbeit beinhaltet experimentelle Untersuchungen zur neuroprotektiven Wirkung des körpereigenen Lipids L-alpha-Lysophosphatidylinositol (LPI). Die Vermittlung dieser Wirkung soll durch den zentralnervös exprimierten G-Protein-gekoppelten Rezeptor 55 (GPR55) erfolgen. Als Modelsystem diente die organotypische hippocampale Schnittkultur (OHSC) der Ratte, welche exzitotoxisch mittels N-Methyl-D-Aspartat (NMDA) geschädigt wurde, um Neurodegeneration zu initiieren. Die Inkubation mit LPI nach NMDA-Schädigung reduzierte die Anzahl toter Neurone und die der Mikroglia in der Körnerzellschicht des Gyrus dentatus. Ein Clodronat-induzierter Verlust der Mikroglia und die siRNA-vermittelte Herabregulation von Gpr55 hoben jeweils den neuroprotektiven Effekt von LPI in der OHSC auf. Diese Beobachtungen wiesen auf eine Mikroglia- und GPR55 abhängige Neuroprotektion hin. LPI wirkte zudem synergistisch und verstärkte die (bekannter Maßen) durch Cannabinoide induzierte und über den Cannabinoid Typ 1 Rezeptor vermittelte Neuroprotektion. Ferner wurde Gpr55 mittels qPCR in Mikroglia und Astrozyten nachgewiesen. LPI steuerte außerdem die Expression von Gpr55 in Mikroglia und beeinflusste deren Migrationsverhalten. Die vorliegenden Ergebnisse machen deutlich, dass LPI in einem in vitro Modellsystem zur Untersuchung des sekundären neuronalen Schadens protektiv wirkt und für die Vermittlung dieser Neuroprotektion Mikroglia und GPR55 in Frage kommen.

Puberty is a critical period for sexual maturation during which the sex-specific reorganization and remodelling of the pubertal brain facilitate sex biases in stress sensitivity. Pubertal (i.e., six-week-old) CD-1 mice treated with the bacterial endotoxin lipopolysaccharide (LPS; 1.5 mg/kg body weight, ip) show several sex-specific changes to the neuroendocrine and behavioural systems of several reproductive and non-reproductive functions. One promising explanation for the elusive mechanisms driving the sex-specific outcomes of pubertal immune challenge may lie in the cascade of neuroimmune events induced by this systemic immune stressor. This doctoral thesis tested the hypothesis that sex-specific responses of the pubertal neuroimmune network contribute to sex differences in the enduring outcomes of pubertal immune challenge on hippocampus-dependent cognitive processes. Male and female CD-1 mice are equally vulnerable to enduring impairments in spatial memory following pubertal LPS exposure. Across brain regions for cognition and stress regulation, pubertal LPS treatment alters baseline sex differences in microglial expression and morphology in a sex-dependent manner. The temporary female-specific increase in whole-brain blood-brain barrier permeability during LPS-induced sickness may have facilitated the apparent female bias in LPS-induced changes to pubertal microglia. In the context of sex- and region-specific residual effects of pubertal LPS-induced sickness on microglial expression and morphology, pubertal LPS treatment may accelerate certain neurodevelopmental processes in males but not females. The innate sex differences in the pubertal neuroimmune network highlighted by these studies underscore how a systemic immune challenge precipitates sex biases in immune-mediated disorders of brain and behaviour during adulthood.

Increased neuroinflammation has been shown in individuals diagnosed with schizophrenia (SCHZ). This study evaluated a novel immune modulator (PD2024) that targets the pro-inflammatory cytokine tumor necrosis factor-alpha (TNFα) to alleviate sensorimotor gating deficits and microglial activation employing two different rodent models of SCHZ. In Experiment 1, rats were neonatally treated with saline or the dopamine D2-like agonist quinpirole (NQ; 1 mg/kg) from postnatal day (P) 1-21 which produces increases of dopamine D2 receptor sensitivity throughout the animal's lifetime. In Experiment 2, rats were neonatally treated with saline or the immune system stimulant polyinosinic:polycytidylic acid (Poly I:C) from P5-7. Neonatal Poly I:C treatment mimics immune system activation associated with SCHZ. In both experiments, rats were raised to P30 and administered a control diet or a novel TNFα inhibitor PD2024 (10 mg/kg) in the diet from P30 until P67. At P45-46 and from P60-67, animals were behaviorally tested on auditory sensorimotor gating as measured through prepulse inhibition (PPI). NQ or Poly I:C treatment resulted in PPI deficits, and PD2024 treatment alleviated PPI deficits in both models. Results also revealed that increased hippocampal and prefrontal cortex microglial activation produced by neonatal Poly I:C was significantly reduced to control levels by PD2024. In addition, a separate group of animals neonatally treated with saline or Poly I:C from P5-7 demonstrated increased TNFα protein levels in the hippocampus but not prefrontal cortex, verifying increased TNFα in the brain produced by Poly I:C. Results from this study suggests that that brain TNFα is a viable pharmacological target to treat the neuroinflammation known to be associated with SCHZ.

Although the central nervous system was long perceived as the ivory tower without immune entities, there is growing evidence that the immune and nervous systems are intimated connected. These two systems have been shown to communicate both cellularly and molecularly under physiological and pathological conditions. Despite our increasing understanding of the interplay between these two systems, there are still numerous open questions. In this thesis, I address such unanswered questions related to: the role of microglia and their mechanism in contributing to pathologies in Rett syndrome; the beneficial effects of T-cell secreted cytokines in supporting social brain function; the evolutionary link of the interactions between the nervous and immune systems; the transcription regulation of a subset of microglia population in common neurodegenerative diseases. Collectively, the current thesis is focused on the joint frontier of bioinformatics and experimental work in neuroimmunology. A multifaceted approach, that includes transcriptomics, genomics and other biomolecular modules, was implemented to unearth signaling pathways and mechanisms underlying the presenting biological phenomena. The findings of this thesis can be summarized as follows: 1) MeCP2 acts as a master regulator in the transcriptional repression of inflammatory stimuli in macrophages; 2) T-cell secreted IFN-γ supports social brain function through an evolutionally conserved interaction between the immune and nervous systems; 3) The APOE-TREM2 pathway regulates the microglia phenotype switch in neurodegenerative diseases. Provided that recent technologies allow for readily manipulating the immune system, the findings presented herein may create new vistas for therapeutic interventions in various neurological disorders.

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