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Researchers identify schizophrenia’s ‘master-key’ gene.

Many genes responsible for the creation of synaptic proteins have previously shown to be strongly linked to schizophrenia and other brain disorders, however, until now the reasons have not been understood.  Now, researchers from Cardiff University have identified a critical function of what they believe to be schizophrenia’s ‘Rosetta Stone’ gene that could hold the key to decoding the function of all genes involved in the disease.  The team state that the breakthrough has revealed a vulnerable period in the early stages of the brain’s development that they hope can be targeted for future efforts in reversing schizophrenia.  The study is published in the journal Science.

Previous studies show that schizophrenia affects around 1% of the global population and an estimated 635,000 people in the UK will at some stage in their lives be affected by the condition. The projected cost of schizophrenia to society is around £11.8 billion a year.  The symptoms of schizophrenia can be extremely disruptive, and have a large impact on a person’s ability to carry out everyday tasks, such as going to work, maintaining relationships and caring for themselves or others.

The gene identified in the current study is known as ‘disrupted in schizophrenia-1’ (DISC-1). Earlier studies have shown that when mutated, the gene is a high risk factor for mental illness including schizophrenia, major clinical depression and bipolar disorder.  The aim of the current study was to determine whether DISC-1’s interactions with other proteins early on in the brain’s development had a bearing on the brain’s ability to adapt its structure and function, also known as ‘plasticity’, later on in adulthood.

The results showed that in order for healthy development of the brain’s synapses to take place, the DISC-1 gene first needs to bind with two other molecules known as ‘Lis’ and ‘Nudel’.  The experiments in mice revealed that by preventing DISC-1 from binding with these molecules prevents cortical neurons in the brain’s largest region from being able to form synapses.  The ability to form coherent thoughts and to properly perceive the world is damaged as a consequence of this.

The data findings also showed that preventing DISC-1 from binding with ‘Lis’ and ‘Nudel’ molecules when the brain was fully formed had no effect on its plasticity. However, the researchers were able to pinpoint a seven-day window early on in the brain’s development, one week after birth, where failure to bind had an irreversible effect on the brain’s plasticity later on in life.

The researchers hypothesize that DISC-1 is schizophrenia’s Rosetta Stone gene and could hold the master key to help unlock the understanding of the role played by all risk genes involved in the disease.  They go on to add that they have identified a critical period during brain development that will assist in testing whether other schizophrenia risk genes affecting different regions of the brain create their malfunction during their own critical period.  The team state that 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, they hope, could one day help to prevent the manifestation or recurrence of schizophrenia symptoms altogether.

The lab surmise that their study provides strong experimental evidence that subtle changes early on in life can lead to much bigger effects in adulthood. They go on to conclude that this helps explain how early life events can increase the risk of adult mental health disorders like schizophrenia.

Source:  Cardiff University

 

Dendritic development in animals transiently expressing DISC1cc.  Example of L2/3 cell dendrites showing spines and dendritic order. Scale bar=10 microns. Growth  in  dendrites  charted  as  an  increase  in  internodal  distances.  The  change  in  median  internodal  distance  is  given  as  percentage  of  the  internodal distance at the start of the period.  Adult cortical plasticity depends on an early postnatal critical period.   Hardingham et al 2015.
Dendritic development in animals transiently expressing DISC1cc. Example of L2/3 cell dendrites showing spines and dendritic order. Scale bar=10 microns.
Growth in dendrites charted as an increase in internodal distances. The change in median internodal distance is given as percentage of the internodal distance at the start of the period. Adult cortical plasticity depends on an early postnatal critical period. Hardingham et al 2015.

 

 

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