Abstract
Parental microglial induced neuroinflammation, triggered by bacterial- or viral infections, can induce neuropsychiatric disorders like schizophrenia and autism to offspring in animal models. Recent investigations suggest that microglia, the resident immune cells of the brain, provides a link between neurotransmission, immune cell activation, brain inflammation and neuronal dysfunction seen with the offspring. Relatively little is known about how reduction of brain inflammation and restoration of glial function are associated with diminution of brain degeneration and behavioral deficits in offspring. Increased mGluR5 expression and the long-lasting excitotoxic effects of the neurotoxin during brain development are associated with the glial dysfunctions. We investigated the relationship of mGluR5 and PBR and how they regulate glial function and inflammatory processes in mice prenatally exposed to LPS (120μg/kg, between gestational days 15 and 17), an inflammatory model of a psychiatric disorder. Using PET imaging, we showed that pharmacological activation of mGluR5 during 5 weeks reduced expression of classic inflammation marker PBR in many brain areas and that this molecular association was not present in LPS-exposed offspring. The post-mortem analysis revealed that the down regulation of PBR was mediated through activation of mGluR5 in astrocytes. In addition, we demonstrated that this interaction is defective in a mouse model of the psychiatric deficit offering a novel insight of mGluR5 involvement to brain related disorders and PBR related imaging studies. In conclusion, mGluR5 driven glutamatergic activity regulates astrocytic functions associated with PBR (cholesterol transport, neurosteroidogenesis, glial phenotype) during maturation and could be associated with neuropsychiatric disorders in offspring.
Highlights
In recent years, metabotropic glutamate receptor subtype 5 has been a growing topic in research for its role in several central and peripheral diseases [1]
We have recently demonstrated that inflammatory processes induced by an infection during gestational period alters expression of glial metabotropic glutamate receptor subtype 5 (mGluR5), and the degree of this alteration is associated with many brain-related disorders as a delay in the reflex development of young pups [13], deficits in social behavior and working memory of adolescent offspring [12] and hypoanxious phenotype in young adults [14]
These studies support an idea that modulation of glial mGluR5 expression during development is one factor involved in the brain-related behavioral disorders which are associated with inflammatory processes during development
Summary
Metabotropic glutamate receptor subtype 5 (mGluR5) has been a growing topic in research for its role in several central and peripheral diseases [1]. Its signaling is mainly associated to Gq/G11 and activates phospholipase C, resulting in hydrolysis of phosphoinositides and generation of inositol 1,4,5-triphosphate and diacylglycerol This typical pathway leads to calcium mobilization and activation of protein kinase C [2]. The activation of mGluR5 reduces the amount of reactive glial cells, brain inflammation and neurotoxicity [10, 12, 16, 17] These anti-inflammatory properties are associated with a lower level of brain degeneration and a reduction of behavioral deficits. This led to hypothesis of the possible underlying interaction between mGluR5, inflammation and glial function
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