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

The devastating effects of the COVID-19 pandemic have underscored the significant threat that infectious diseases pose to our society. Pregnancy represents a period of heightened vulnerability to 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), which is triggered by viral or bacterial infections, and increased risk for neurodevelopmental disorders such as autism and schizophrenia. Genetic and environmental factors may contribute to the overall risk. Therefore, 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 is focused on the interaction between MIA and cannabis use during adolescence, considering the role of the endocannabinoid (eCB) system in neurodevelopment and in neurodevelopmental disorders. The eCB system, crucial for fetal brain development, may be disrupted by MIA, leading to adverse outcomes in adulthood. Recent research indicates the eCB system's significant role in the pathophysiology of neurodevelopmental disorders in preclinical models. However, findings on adolescent cannabinoid exposure in MIA-exposed animals have revealed unexpected complexities, with several studies failing to support the exacerbation of MIA-related abnormalities. In this review, we delve into the functional implications of the eCB system in MIA models, emphasizing the role of 2-AG (2-arachidonoylglycerol) signaling in synaptic plasticity and neuroinflammation and its relevance to the two-hit model of schizophrenia.