Scientists believe they are on the verge of a breakthrough in the treatment of autistic spectrum disorders (ASC), after finding a genetic mutation that disrupts communication between brain cells.

The study, led by Dr Johanna Montgomery at the Centre for Brain Research at the University of Auckland, found that a protein that is mutated in people with ASCs affects data transfer in the brain through synapses, which could explain some of the cognitive and behavioural difficulties that people with the condition experience.

Dr Montgomery and her team investigated synapses, which are the structures that enable brain cells to communicate with each other. This cell to cell communication is vital for a healthy brain, and it underlies how we learn, remember, move and sense. Information is transmitted from one neuron to another at synapses. This process is mediated by several families of protein, some of which form the bedrock of the synapse on the ‘listening’ side. Dr Montgomery’s team investigated one of these proteins, Shank3, because it has been identified as vital to the communication process between two neurons, and is known to be mutated in ASDs. 

Usually, the more two neurons ‘talk’ to one another, the larger and more efficient the synapse becomes. However, the researchers found that in neurons carrying ASD mutations in the Shank3 protein, cell-cell communication was not only weaker than usual, but that repetition didn’t strengthen or stabilise the synaptic connection.

Further investigation revealed that Shank3, when healthy, forms complexes with two other types of protein, neurexin and neuroligin, which are also frequently mutated in ASCs. These complexes act to physically bridge the synaptic gap and can transmit information from the receiving or ‘listening’ side of the synapse to the transmitting side. This ‘backward’ flow of information completes a feedback loop between the two neurons which is likely to be responsible for the strengthening of the connection.

Dr Montgomery and her team believe that the Shank3/neurexin/neuroligin complex is critical to the ability of neurons to effectively transfer information across the synapse to ensure the correct messages get through at the appropriate strength. This complex of proteins helps both sides of the synapse co-ordinate to improve the efficacy of messaging, and this in turn increases the likelihood of successful transmission in future. Therefore, ASC mutations are preventing this efficient transfer of information between neurons, which likely underlies the behavioural and cognitive changes that occur in people with ASCs.

Researchers also found that the opposite occurs when neurons express multiple copies of the Shank3 gene, as is known to occur in Asperger’s syndrome. In this case the communication between neurons gets much stronger, increasing their efficacy and providing a possible mechanism for the enhanced cognitive function that is associated with this syndrome.

“This is really exciting stuff,” said Dr Montgomery. “We’re moving beyond simply what happens in ASCs and starting to understand how it happens. Now we have identified the problems that these mutated proteins cause, we have a focus for developing treatments to offset the synaptic deficits that result.  That’s the next step.” 

The results are published in the Journal of Neuroscience.