Schizophrenia: Identification of ‘Rosetta Stone’ Gene

DISCOVERY of a key role for the protein ‘disrupted in schizophrenia 1’ (DISC1) during a critical period of neural development shortly after birth may lead to new insights into several mental illnesses. Mutations in the gene encoding DISC1 (DISC1) have been previously associated with a high risk of developing schizophrenia, major clinical depression, and bipolar disorder, although the mechanism(s) underlying this increased risk is not yet understood. Prof Kevin Fox, leader of the research team from Cardiff University’s School of Biosciences, Cardiff, UK, emphasised the importance of the new findings: “We believe that DISC1 is schizophrenia’s Rosetta Stone gene and could hold the master key to help us unlock our understanding of the role played by all risk genes involved in the disease.”

The researchers investigated the implications of disrupted DISC1-mediated protein–protein interactions and signalling during development by treating neonatal mice with the protein-releasing drug tamoxifen, and then observing the effects on the brain’s plasticity in adulthood. Healthy development of the brain’s synapses was revealed to be dependent on the interaction of DISC1 with the proteins Lis and Nudel during a 7-day window early in development (1 week after birth), with the disruption of DISC1 binding/signalling via tamoxifen treatment preventing cortical neurons from forming synapses within the brain’s largest region, which led to an irreversible effect on the brain’s plasticity later in life. This impaired synaptic development may negatively impact on the ability of an individual to perceive, comprehend, and interact properly with their environment, which is a feature of schizophrenia. In contrast to its effects during the early stages of development, disruption of DISC1 binding/signalling when the brain was fully formed did not affect its neural plasticity.

Prof Fox summarised the implications of the findings: “The potential of what we now know about this gene is immense. We have identified a critical period during brain development that directs us to test whether other schizophrenia risk genes affecting different regions of the brain create their malfunction during their own critical period. The challenge ahead lies in finding a way of treating people during this critical period or in finding ways of reversing the problem during adulthood by returning plasticity to the brain. This, we hope, could one day help to prevent the manifestation or recurrence of schizophrenia symptoms altogether.”

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