Study links the breakdown in brain cell development and the risk of Schizophrenia

A new study revealed that the genetic disruption of specific cell processes essential in brain development is associated with several psychiatric disorders.

The study was jointly led by Dr. Andrew Pocklington from the Division of Psychological Medicine and Clinical Neurosciences at Cardiff University and Dr. Eunju Jenny Shin from the Neuroscience and Mental Health Research Institute at Cardiff University and now at Keele University.

Scientists studied the process called Neurogenesis in vitro using human pluripotent stem cells. Neurogenesis is the process by which new neurons are formed in the brain.

During this process, scientists found several sets of genes activated in both in vitro and human fetal brains. Interestingly, each set plays a distinct functional role. 

Scientists later showed that the genetic risk factors that cause schizophrenia and other psychiatric disorders were highly concentrated in these sets.

Dr. Shin said: “To truly understand the root causes of psychiatric disorders, we focused on studying the development of brain cells. The knowledge gained through this approach may ultimately help guide the development of novel therapies or help explain why some individuals respond to some treatments but not others.”

“In vitro experiments showed that when activation of these sets is disrupted, the shape, movement and electrical activity of developing brain cells are altered, linking changes in these properties to disease.”

Disorders linked to disruption of these genes included both early-onset conditions and, more surprisingly, conditions with a later onset (bipolar disorder, major depression) for which disruption of early brain development is not generally thought to play a significant role.

This raises whether some of these genes remain active later in life and contribute to mature brain function, where they can potentially be targeted therapeutically.

Dr. Pocklington said: “Previous studies have shown that genes active in mature brain cells are enriched for common genetic variants contributing to schizophrenia. Much of this enrichment was captured by the early developmental gene sets, which seem to contain a greater burden of common genetic risk factors.”

“This suggests that some biological pathways first switched on in the early prenatal brain may remain active in later life, with genetic variation in these pathways contributing to disease by disrupting both development and mature brain function.”

Dr. Shin said: “Although much remains to be uncovered, our findings provide valuable insight into the developmental origins of psychiatric disorders such as schizophrenia.”

Journal Reference:

1. Sanders, B., D’Andrea, D., Collins, M.O. et al. Transcriptional programs regulating neuronal differentiation are disrupted in DLG2 knockout human embryonic stem cells and enriched for schizophrenia and related disorders risk variants. DOI: 10.1038/s41467-021-27601-0