Long-term effects of early systemic immune challenge on CNS function

• Applicant: Privatdozent Dr. Thomas Blank
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: from 2011 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 190888409

The immature brain can be exposed to inflammation in connection with systemic viral or bacterial infection shortly after birth. Inflammation of the brain has often long-term consequences and can increase the risk to develop a variety of neurological and neuropsychiatric disorders, including autism spectrum disorders, schizophrenia, multiple sclerosis and cognitive impairment. So far, the picture is incomplete and mechanistic data scarce. During the neonatal time window, we elicited increased type I interferon (IFN) signaling by repeated application of the viral mimetic polyriboinosinic-polyribocytidylic acid (poly(I:C)) to the periphery of mice. This treatment induced type I IFN-dependent gene expression particularly in brain endothelia. When these mice had reached adolescence they displayed reduced cognitive abilities and impaired social behavior. We have chosen this particular time period because many symptoms of neurodevelopmental and neuropsychiatric disorders including behavioral abnormalities emerge in humans during the adolescent phase. At present, it is largely unknown how long-lasting behavioral changes in response to early, systemic type I IFN exposure can manifest themselves within the CNS. In adolescent mouse brains, we observed lasting microglia activation in response to a neonatal immune challenge. This resembles the situation found after neonatal brain inflammation in human infants, where a diffuse activation of microglia has been reported. With the present research proposal, we will be able to generate a more complete picture on the cellular processes leading to long-term CNS effects of peripheral neonatal inflammation. We will achieve this central goal by interfering with different parts of the type I IFN signalling chain in mice that are lacking the respective receptor of type I IFN (IFNAR) selectively on neurons, astrocytes, myeloid cells, brain macrophages or brain endothelial cells. These insights will be essential to obtain an understanding of potential detrimental signaling cascades as a target for therapeutic interventions. The expected results should further prove helpful for the identification of biomarkers that predict the occurrence of neurological and psychiatric diseases later in life.

• DFG Programme: Research Grants