Complement Pathway Changes Associated with Psychotic Experiences

Post by: Stephanie Williams

What's the science?

The complement system is a complex system of proteins involved in an immune system cascade in response to pathogens. However, this system can also play a regulatory role in the brain. There is scientific evidence that pro-inflammatory processes precede psychosis, as well as other psychiatric disorders. Still, it is unclear what changes occur in the complement pathway and at what period in development those changes occur. This week in Molecular Psychiatry, Föcking and colleagues identified changes in plasma complement pathway proteins that are associated with psychotic experiences as well as changes in the complement pathway that follow exposure to stress in mice.

How did they do it?

To understand the changes in the complement system that are associated with psychosis, the authors analyzed plasma protein expression levels of adolescents at age 12 who went on to report psychotic experiences at age 18. Adolescents who experienced psychotic symptoms when they were 18 (but not when 12) were referred to as the psychotic experiences group (n=64). The authors compared the expression of complement proteins in individuals with psychotic experiences to individuals in an age-matched control group.

The authors also conducted a chronic social defeat stress (CSDS) experiment with mice to investigate the relationship between exposure to stress and protein expression changes in the complement system. They briefly introduced male mice (“resident” mice) to a new aggressor mouse (“intruder” mice) for five minutes, before having the intruder mice stay in the same cage on the opposite side of a partition (this is a known stressor for mice). After ten days of this stressor, some mice began avoiding new mice (social avoidance behavior). The authors then compared the expression of different plasma proteins between the group of stressed mice and a control group.

What did they find?

Six of the twenty-nine proteins the authors investigated in human adolescents were significantly upregulated in the psychotic experiences group at age 12. This result suggests that alterations in the expression of proteins in the complement pathway are associated with psychotic experiences. Analysis of protein expression following CSDS in mice showed changes in ten complement proteins, seven of which were upregulated. This finding suggests that alterations in the expression of protein in the complement pathway may be related to exposure to stress.

What's the impact?

This is the first study to investigate complement proteins in a murine model of psychosocial stress. The authors built on previous work in which they showed that the expression of some complement proteins is different between individuals who experience psychotic symptoms and individuals who do not. Here, they reviewed a more comprehensive set of complement proteins, and found that changes in the complement system as early as 12 are associated with psychotic experiences. Their findings advance our understanding of the role of the complement system in psychiatric disorders, and suggest complement pathway protein expression could be a useful measure in predicting psychosis risk.

Föster et al. Complement pathway changes at age 12 are associated with psychotic experiences at age 18 in a longitudinal population-based study: evidence for a role of stress. Molecular Psychiatry (2019).Access the original scientific publication here.