Deciphering the biology behind psychiatric risk genes

Genetic studies that scan the genomes of psychiatric patients are becoming increasingly good at identifying ‘risk genes’ associated with disorders such as schizophrenia, autism and intellectual disability. However, we still know very little about the biological actions and pathways that are being genetically encoded within these risk genes. Understanding the biology behind the vulnerability to psychiatric disorders is especially important if we hope to reverse these mechanisms through therapeutic intervention.

Excitingly, numerous genomic studies in psychiatric populations point towards the synapse, and particular synaptic risk genes FMRP, CYFIP1 and ARC, as a major component in causing these disorders. We already know a lot about the importance of synapses, which orchestrate the connections made between nerve cells and support communication within the brain. However, questions remain: ‘What do these particular synaptic risk genes do?’, ‘How do they influence synaptic biology as proteins?’ and most importantly, ‘How are these biological pathways relevant to psychiatric disorders?’

Progress towards answering these questions has now been made by researchers at Cardiff. Scientists based in the Neuroscience and Mental Health Research Institute have experimentally manipulated one of these synaptic risk genes, CYFIP1. They found that that the deletion of the gene CYFIP1 leads to considerable thinning of myelin sheaths, which cover nerve cells and support the rapid communication across parts of the brain (published in Nature Communications, 2019).

Although many genes likely contribute to psychiatric disorders, CYFIP1 is especially interesting. Work in Cardiff at the MRC Centre for Neuropsychiatric Genetics and Genomics, has already shown that patients with psychiatric disorders have a prominent genetic change known as a Copy Number Variants (CNV), where sections of DNA are deleted from chromosomes. Often these CNVs span dozens of genes, so it is extremely difficult to know how each of these gene contributes to the disorder. However, deletions on chromosome 15, known as 15q11.2, are different: they span the CYFIP1 gene and only 3 others.

Using the very latest gene-editing technologies, living brain cells were created with only copy of the CYFIP1 gene, instead of the normal complement of two copies. This deletion model very closely mirrors the genetics of people with the CNV deletion. Cardiff researchers found abnormalities in myelin, an insulating layer around nerve cells, and this appeared to originate from oligodendrocytes, a type of brain cell involved in creating these myelin sheaths. Unusually, the exact same findings were discovered by another group in Switzerland (and also published in the same issue of Nature Communications, 2019).

Not only was the wiring of brain cells found to be altered, but only having one copy of CYFIP1 led to a profound change in the way nerve cells support behaviour and higher brain functions like cognition. Brains with one copy of CYFIP1 resulted in more rigid, and less flexible, behaviour in cognitive tasks, a common symptom in people with psychiatric disorders.

Building on these findings, the same research group in Cardiff are now looking for myelin abnormalities in people with the 15q11.2 deletion using the very latest brain-imaging techniques and trying to work out the exact mechanism that links CYFIP1 to myelin abnormalities, with the aim of reversing its effects.

Also, what about the other synaptic risk genes that have been identified, FMRP and ARC?

The deletion of the FMRP gene single-handedly causes Fragile X Syndrome, a severe psychiatric disorder in its own right, but one that also overlaps greatly with autism and intellectual disability. We already know a lot about the effects of deleting the FMRP gene on nerve cells and behaviour, and it appears to lead to similar wiring changes as the deletion of CYFIP1. This might not come as a surprise, given that FMRP binds to CYFIP1, which means they likely to share many of the same biological pathways (see diagram).

ARC protein at the synapse is vital in supporting the biological changes required for learning and memory. Researchers at Cardiff have also shown that Arc has an important role in the extinction of memory, a learnt form of uncoupling or diminished responding, which is often missing in people with psychiatric disorders. Yet it is far less clear how ARC and its wider network of related proteins, might increase psychiatric vulnerability, and is still being investigated.

As neuroscientists uncover these important biological pathways, the more we can move away from regarding the brain as a mysterious black box. Yet more needs to be done in translating these scientific discoveries into viable treatment options that actually reach the clinic and improve patient’s quality of life. Currently, most treatments simply ‘manage’ the symptoms of psychiatric disorders, and in no way reverse the underlying disease mechanisms.

Whilst societal shifts have helped decrease the stigma around mental health, we are only just starting to comprehend the extent and scale of this epidemic. Scientists must now harness this momentum, in deciphering the biology behind psychiatric risk genes, and truly make a difference.

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