Scientists at Cardiff University have discovered new links between the breakdown in brain cell development and the risk of schizophrenia, representing a ‘major step forward’ in the hunt for the developmental origins of psychiatric disorders.

The findings, which are published in the journal Nature Communications, reveal that genetic disruption of specific cell processes crucial to brain development is linked to disease risk in a wide range of psychiatric disorders.

As co-author Dr Pocklington from the Division of Psychological Medicine and Clinical Neurosciences explains: “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.”

“To truly understand the root causes of psychiatric disorders,” adds co-author Dr Shin, “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.”

The findings may lead to novel therapies 

The scientists studied the birth and early development of human brain cells (known as neurogenesis) in vitro using human pluripotent stem cells, and noticed several sets of genes that are switched on both in vitro and in human foetal brain.

Each set appeared to play a distinct functional role and the researchers showed that genetic risk factors contributing to schizophrenia and other psychiatric disorders were highly concentrated in these sets.

“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,” explains Dr Shin.

Further research now needed to explore long-term effects on the brain

Disorders linked to disruption of these genes included both early onset conditions (developmental delay, autism and ADHD) 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 large role.

This prompted the researchers to consider whether some of these genes, which are first switched on long before birth, 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 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.”

The researchers say the findings provide “valuable insight into the developmental origins of psychiatric disorders”, but more research is now needed to map out the full range of developmental processes disrupted in different psychiatric disorders and explore their longer-term effects on the brain.