Inflammatory mechanisms in a two-hit mouse model of neurodevelopmental disease

• Applicant: Professor Dr. Harald Engler
• Subject Area: General, Cognitive and Mathematical Psychology
• Term: from 2014 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 264577147

Increasing evidence suggests that early-life programming effects may play an essential role in the pathogenesis of neuropsychiatric diseases that comprise components of abnormal brain development, including schizophrenia, autism, and bipolar disorder. Using a translational mouse model, we have recently shown that combined exposure to prenatal immune challenge and peripubertal stress induces synergistic pathological effects on adult behavioral functions and neurochemistry. In this two-hit model, offspring subjected to both environmental insults showed marked signs of neuroinflammation characterized by microglia overactivation and hypersecretion of brain inflammatory cytokines. The overall objective of the proposed project is to investigate the contribution of inflammation to the development of behavioral abnormalities and neuropathological changes, with the long-term goal to identify potential preventative approaches or therapeutic targets for neuropsychiatric diseases. Our general hypothesis is that inflammation plays a key role in the priming of neurodevelopmental disease and, accordingly, interference with inflammatory events by using either cytokine-neutralizing antibodies during prenatal immune challenge or a selective inhibitor of NF-kB activation during peripubertal stress exposure has protective effects in this model.

• DFG Programme: Research Grants
• International Connection: Switzerland
• Co-Investigators: Professor Dr. Urs Meyer; Professor Dr. Manfred Schedlowski