Mental health disorders in offspring linked to genetic and environmental factors affecting birth parent during pregnancy

The World Health Organization notes that about one in seven young people aged 10 – 19 years old have a juvenile mental health disorder. These disorders include depression, bipolar disorder, and schizophrenia. The exact reason why and how these disorders develop is still elusive, but they are thought to arise from a combination of genetic and environmental factors, including viral infection, pollution, and diet. Understanding the mechanisms underlying these disorders will help with their prevention and treatment. 

In a new preclinical study published in Brain Behavior and Immunity, PhD candidate Micaël Carrier (Tremblay Lab; pictured) and co-authors used models to look at mental health disorders in offspring born to a birth parent who had a genetic immune issue and who contracted a viral infection during pregnancy. (The birth parent model had a genetic issue that made them deficient in fractalkine, a protein that allows for proper communication between neurons and microglia.) They found that such a pregnancy could lead to behavioural deficits in both female and male offspring.

The male offspring models developed behaviours related to schizophrenia, which had also happened to male offspring in previous studies where the birth parent model only had immune challenges. The female offspring models in Micaël’s study, however, showed signs of behaviour associated with mood disorders like anxiety, depression, and bipolar. This behaviour had not been seen in similar previous studies, though it had been described in unrelated research investigating psychological stress.

To understand this new phenotype in the female offspring models, the Tremblay Lab investigated the main immune cell of the brain, microglia, and profiled the models’ genome expressions. Micaël first used an open-source platform to analyze the genome expression data. He then wrote a program using R code that was able to statistically compare the results between controls and the offspring models in his study. This comparison showed results that were not seen with standard statistical tests, including a downregulation of the brain’s GABAergic system. The GABAergic system is often the focus of research aimed at developing pharmaceutical treatments for anxiety and depression. (Lorazepam, a pharmaceutical already on the market, targets this system.) Micaël and his co-authors also found that microglia in the hippocampus were still impaired at adulthood, suggesting the female offspring models’ mental health-like disorders contributed to some immune dysfunction. (Microglia are necessary for proper brain maturation, and previous research has shown that preventing microglia from doing their developmental role causes neurodevelopmental disorder–like behaviours in preclinical models. Also, the hippocampus, a crucial region of the brain for learning and memory, is known to be altered in depression.)

Using confocal microscopy, Micaël and his team showed that the microglia from female offspring models were also physically different. This told the researchers that the cells had been permanently altered in the mental health-like condition affecting the models; this alteration would have affected the cells’ efficacy in performing their roles and could possibly explain the behavioral deficits seen.

This study counted on the participation of many Tremblay Lab members, including first-author Micaël, a PhD candidate from Laval University and a visiting researcher at UVic; Fernando González Ibáñez, a PhD candidate from Laval University and a visiting researcher at UVic; and Dr. Katherine Picard, who recently obtained her PhD from Laval University under the supervision of Dr. Marie-Ève Tremblay and is currently a research assistant at the Tremblay Lab.