Maternal Immune Activation and Endocannabinoid System: Focus on Two-Hit Models of Schizophrenia

: The devastating effects of the COVID-19 pandemic have underscored the significant threat infectious diseases pose to our society. Pregnancy represents a particularly vulnerable period for infections, which can compromise maternal health and increase the risk of neurodevelopmental disorders in offspring. Preclinical and clinical investigations suggest a potential association between maternal immune activation (MIA), triggered by viral or bacterial infections, and the increased risk for neurodevelopmental disorders such as autism and schizophrenia. Genetic and environmental factors might contribute to the overall risk. Hence, the two-hit hypothesis of schizophrenia suggests that MIA could act as a first trigger, with subsequent factors, such as stress or drug abuse, exacerbating latent abnormalities. A growing body of research focuses on the interaction between MIA and cannabis use during adolescence, considering the role of the endocannabinoid system in neurodevelopment and in neurodevelopmental disorders. The endocannabinoid system, crucial for fetal brain development, may be disrupted by MIA, leading to adverse outcomes in adulthood. Recent research indicates the endocannabinoid system's significant role in the pathophysiology of neurodevelopmental disorders in preclinical models. However, findings on adolescent cannabinoid exposure in MIA-exposed animals reveal unexpected complexities, with several studies failing to support the exacerbation of MIA-related abnormalities. This review delves into the functional implications of the endocannabinoid system in MIA models, emphasizing 2-arachidonoylglycerol (2-AG) signaling's role in synaptic plasticity and neuroinflammation, and its relevance to the two-hit model of schizophrenia.