Molecular mechanisms of astrocyte maturation and secretome in neurodevelopmental disorders associated with prenatal inflammation

Neurodevelopmental diseases (NDDs) are a group of disorders affecting brain development; they include intellectual disability (ID), autism spectrum disorder (ASD) and several other conditions characterised by social and cognitive deficits, and symptoms ranging from mild to severe. Pathogenetic causes are still poorly known and therapeutic tools are insufficient. In the last decade, it became clear how brain development and functions are strongly modulated by glial cells. In particular, astrocytes, the most abundant glial cell type, are now recognized to shape synapse formation and function by releasing synaptogenic factors and gliotransmitters during development. In adulthood, they are an integral part of the tripartite synapse. Astrocytes are key active players also in pathological conditions, mediating inflammatory response after brain insult or infection by rapidly acquiring different specific molecular phenotypes that are only beginning to be characterised. Strong research evidence and epidemiological studies indicate that maternal immune activation (MIA) and prenatal inflammation are key concurrent factors for NDDs. Preclinical models show that MIA results in later-in-life alterations in the offspring’s brain structure, such as neurochemical and behavioural abnormalities. We recently showed that elevated proinflammatory cytokines, IL1β and IL6, have detrimental impact on synapse and brain circuit formation. We also demonstrated that pentraxin3 (PTX3), an innate immune molecule, is released by astrocytes and exerts a synaptogenic role under physiological conditions. Moreover, our preliminary results show that MIA affects PTX3 content in the postnatal offspring brain. Besides immune molecules, astrocytes also synthesise neurosteroids, endogenous molecules that modulate neuronal excitability and play important roles in brain development and neuroinflammation. Furthermore, the synthesis of NS can be substantially affected by neuroinflammation. In this scenario, whether prenatal inflammation impacts astrocyte phenotype or their ability to support neuronal cells by adapting the composition of the secretome during development or at adult stage is not known. Based on these premises, we propose to characterise astrocytes in MIA offspring with the aim to i) elucidate if early exposure to an inflammatory environment affects astrocyte development and physiology and ii) identify the precise molecular mechanisms and the signalling pathways involved. Specific aims will be to: 1)Characterise the morphological and molecular phenotype of astrocytes in MIA offspring; 2)Analyse of astrocyte secretome and neurosteroid levels in MIA offspring; 3)Define astrocyte calcium dynamics during brain development in MIA offspring. Our work is expected to provide a detailed picture of astrocyte contribution to NDDs associated with prenatal inflammation and open the way to identify novel targets for therapeutic intervention.