“A single protein may trigger autistic spectrum disorders,” BBC News has reported. According to the news, when mice were bred to lack a protein called Shank3, which normally aids the transfer of signals between brain cells, they showed classic autism-like behaviours, including social problems and repetitive behaviours.

The laboratory study behind this news found that genetically mutated mice that could not make Shank3 had problems at a nerve cell level, which meant that nerve impulses were not conducted normally. In addition, the mice demonstrated social dysfunction in their behaviour that can be likened to some of the social problems demonstrated by people with autism, such as avoiding contact with other mice.

Some forms of autistic spectrum disorder have been linked to problems with Shank3. This study has gone some way to exploring the underlying mechanisms for them. However, autism is a complex disorder, which is likely to have a number of genetic and environmental causes. The study authors have pointed out that only a small proportion of people with autism have a problem with Shank3. Also, as a mouse study, it should be remembered that the direct relevance of these findings to human health are not clear.

 

Where did the story come from?

The study was carried out by researchers from Duke University Medical Centre in the US, the University of Coimbra, the Gulbenkian Science Institute in Portugal, the Massachusetts Institute of Technology and the Broad Institute in the US. The research was funded by the US National Institutes of Health, The Hartwell Foundation and grants from different organisations to individual researchers. The study was published in the peer-reviewed scientific journal Nature.

BBC News has covered the science behind the story well. This is early research and its direct application to human health may be currently limited given that only a small proportion of autism cases are thought to be caused by problems with the particular proteins that were studied.

 

What kind of research was this?

Autism itself and autistic spectrum disorders are neurodevelopmental disorders that manifest themselves through communication deficits, impaired social interaction and repetitive behaviours. Scientists set up this laboratory research to explore the neurological basis of some underlying brain cell problems associated with these diseases.

A number of different genes have been implicated in autistic disorders, including a gene called Shank3. This in turn produces a protein called Shank3, which plays a role in the way that nervous impulses are conducted across brain cells. Problems with the Shank3 gene have been implicated as the cause of some of the major neurological symptoms associated with Phelan-McDermid syndrome (also known as 22q13 deletion syndrome), one type of autistic spectrum disorder.

There are different forms of Shank3 protein and they are all large and complex molecules. They are involved in complex reactions that are not fully understood.

The researchers bred genetically modified mice that were unable to produce the Shank3 proteins, and compared their behaviour to that of regular mice. Some of the genetically modified mice lacked the ability to produce one particular type of Shank3 protein. Others lacked the ability to produce the other forms of the protein.

 

What did the research involve?

The researchers used a series of behavioural tests to investigate the behaviour of the mice that lacked the ability to produce different forms of the Shank3 protein. Mice were assessed when they were young adults, approximately five to six weeks old. Investigators were unaware of the genetic status of the mice, i.e. whether they were the ones that could produce Shank3 normally or whether they were genetically modified.

The behavioural tests involved exposing the mice to a maze and determining how long they spent in open and closed arms of the maze, and how they moved from light to dark parts of the maze. They were also made to walk along a turning rod. Social interaction was determined by assessing the mice’s ability to initiate contact when exposed to each other in a three-chamber social arena.

Brain samples from the mice were then examined. The researchers examined how the levels of a number of known proteins in the synapses were affected by the mutations. They also looked closely at the morphology and physical make up of the brain cells. The researchers attempted to determine exactly where Shank3 proteins were taking effect and measured the strength of the nervous impulses in their brains.

 

What were the basic results?

While the mice with Shank3 mutations performed similarly to normal mice in some behavioural experiments, the mice that could not produce one particular form of the protein, called Shank3B, demonstrated more anxiety-like behaviour and self-injurious grooming, which resulted in skin lesions. These mice also displayed dysfunctional social interaction. They were more likely to avoid time with another mouse, and they were more likely to prefer an empty cage to a compartment containing another animal.

A number of key proteins were also found to be reduced in mice that did not produce Shank3. These proteins are known to play an important role in the way nerve cells conduct their impulses. In mutant mice, some brain cells – those called spiny neurones – were physically different to those seen in normal mice. Shank3 proteins were found to play a critical role in the way that nervous impulses were transmitted in nerve cells in particular sections of the brain.

 

How did the researchers interpret the results?

In conclusion, the researchers say their results show that problems in the Shank3 gene can result in a number of different functional problems, which may in turn be linked to some of the problems in Shank3-related autistic spectrum disorders. The finding that mice with a mutation in this region demonstrated socially dysfunctional behaviour suggests that this gene may be playing a causal role.

 

Conclusion

This is interesting laboratory research that paves the way for future studies into the neurobiology of autism and related disorders. There are several points to keep in mind when interpreting the findings:

The study was in mice, so these findings have only limited direct relevance to humans. The human brain is more complex than that of a mouse. Whether these processes occur in exactly the same way has yet to be established. The researchers themselves note that the mice in their study had mutations in the Shank3 gene that were not exactly the same as those implicated in autistic diseases in humans.

Autism and the autistic spectrum disorders are complex, and a range of different genetic mutations have been implicated as potential contributory factors. The BBC has rightly quoted one of the lead researchers as saying that only a small percentage of people with autism have mutations in Shank3, therefore the key to autism has not yet been found. Other proteins involved in synaptic function may be involved in autistic spectrum disorders. Further studies will be needed to investigate their roles.

It is unclear how the findings inform the development of treatments for autism, given that the findings relate to only one gene implicated in similar disorders in mice.

The findings of this study will be of interest to scientists in this field. But it should be remembered that this was preliminary research into just one gene implicated in a complex disorder that is thought to have several genetic and environmental causes.

Also, given that this was research in mice it is difficult to extrapolate the findings to humans or to make claims about whether this is the key to autism. Other research has identified that a range of genes can be implicated in autistic disorders. Therefore there will be no single key that will unlock our understanding of this disease.