The dual hit hypothesis of schizophrenia

Schizophrenia, a complex psychiatric disorder, significantly affects social and professional life. It typically emerges in early adulthood, and its symptomatology is classified into positive symptoms (hallucinations and delusions), negative symptoms (flattened emotion, social withdrawal, reduced motivation), mood symptoms and cognitive deficits. Schizophrenia is thought to arise from neurodevelopmental dysfunctions that may be caused by an abnormal activity of the immune system, possibly triggered by a combination of genetic and environmental factors. Understanding these neurobiological mechanisms, and the role of and interaction between various risk factor, is crucial for prevention and innovative treatment approaches. This can be studied in animal models.My thesis explored the impact of individual and combined schizophrenia risk factors on the main immune cells of the brain, the number of connections between nerve cells and behavior in rats. I observed complex interactions between genetic and environmental risk factors, sometimes being mutually protective, synergistically detrimental or having no combined effect on brain and behavior. Specifically, rats exposed to adolescent social stress exhibited more deleterious effects in the long term compared to rats that were exposed in adulthood. Additionally, prenatal infection provided protection against social stress later in life, while genetic predisposition increased the risk of neurodevelopmental and behavioral changes resulting from prenatal infection. In summary, my thesis examined the interplay of genetics and environment in schizophrenia, proposing that immune system changes, especially in microglial cells, influenced early brain development, leading to later-life changes in the number of connections between nerve cells and behavior changes