Link Between Brain Cell Development and Schizophrenia Uncovered

Dr Rob Hicks

January 17, 2022

Scientists from Cardiff University have furthered current knowledge regarding how schizophrenia and other mental health disorders arise, through their discovery of new links with brain cell development.

Brain development is a "complex choreography" of cell proliferation, specification, growth, migration and network formation, say the authors of a new study published in Nature Communications . Their research demonstrates for the first time how genetic disruption of specific cell processes vital to brain development is linked to the risk of disease in a broad range of mental health disorders.

The authors explained that coordinated programs of gene expression are known to drive brain development, but that previously it has been unclear which transcriptional programs, in which cell-types, are affected in neuropsychiatric disorders such as schizophrenia.

Dr Andrew Pocklington from the division of psychological medicine and clinical neurosciences at Cardiff University said: "Genetic factors play a significant role in determining a person’s risk of developing psychiatric disorders. Uncovering biological processes impacted by these genetic risk factors is a major step towards understanding the causes of disease."

Cell Development Changes Linked to Disease

Co-author Dr Eunju Jenny Shin from the Neuroscience and Mental Health Research Institute at Cardiff University, who is now at Keele University, explained: "To truly understand the root causes of psychiatric disorders, we focused on studying the development of brain cells."

Using in vitro human pluripotent stem cells, they identified several sets of genes that are switched on during neurogenesis, with each set playing a distinct functional role. Within these sets, the researchers demonstrated that genetic risk factors contributing to schizophrenia and other mental health disorders were highly concentrated.

Dr Shin said: "In vitro experiments showed that when activation of these sets is disrupted, the shape, movement and electrical activity of developing brain cells is altered, linking changes in these properties to disease."

The authors commented that surprisingly it wasn’t only early-onset conditions, such as ADHD, autism, and developmental delay, that were linked to disruption of these genes, but also later-onset conditions, where early brain development is not generally thought to play a role, such as depression and bipolar disorder.

Potential for Future Novel Therapies

Their research raises the question as to whether some of these genes, which are first switched on long before birth, remain active later in life and thereby contribute to mature brain function. If so, then this raises the possibly that they could be targeted therapeutically.

"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," said Dr Shin.

"Previous studies have shown how genes active in mature brain cells are enriched for common genetic variants contributing to schizophrenia. Although early developmental gene sets seem to contain a greater burden of common genetic risk factors," Dr Pocklington said. "This suggests that some biological pathways first switched on in the early pre-natal 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 concluded by saying: "Although much remains to be uncovered, our findings provide valuable insight into the developmental origins of psychiatric disorders such as schizophrenia."

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