Scientists have discovered new links between the breakdown in brain cell development and the risk of schizophrenia and other psychiatric disorders.

Genetic risk factors are known to disrupt brain development in a number of these disorders, but little is known about which aspects of this process are affected.

This research is the first time that genetic disruption of specific cell processes crucial to brain development has been linked to disease risk in a wide range of psychiatric disorders.

The findings are published in the journal Nature Communications.

The scientists studied the birth and early development of human brain cells – a process known as neurogenesis – in vitro using human pluripotent stem cells.

The authors find transcriptional programs expressed during early neurogenesis in vitro and in human foetal cortex that are down-regulated in DLG2−/− lines. Down-regulation impacted neuronal differentiation and maturation, impairing migration, morphology and action potential generation. Genetic variation in these programs is associated with neuropsychiatric disorders and cognitive function, with associated variants predominantly concentrated in loss-of-function intolerant genes.

One of the co-senior authors 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.”

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 raises the question of 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.

The other senior author 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.”

Further work is needed to map out the full range of developmental processes disrupted in different psychiatric disorders and explore their longer-term effects on the brain.

https://www.nature.com/articles/s41467-021-27601-0

http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Ftranscriptional_13&filter=22