The wide range of symptoms associated with autism has long been one of the major challenges for diagnosis and treatment. Researchers suspect this heterogeneity is due to the fact that many different genetic and environmental risk factors can contribute to autism. These different risk factors all probably lead to some common biological mechanisms that actually underlie autism’s core symptoms. Unfortunately we do not yet know what those biological mechanisms are. In 2008, armed with novel technologies and new strategies several research teams reported converging evidence of autism as a disorder of the “synapse.”
The synapse is the point of contact between two neurons. This junction is populated by hundreds of proteins that help maintain and coordinate complex cell to cell communication. Researchers first suspected some of these synaptic proteins may play a role in autism when the genes for several of them, including neuroligin, neurexin and SHANK-3, were found mutated in a small number of cases of autism a few years ago. This suspicion was heightened in 2008 when different teams of researchers from UCLA, Yale and Johns Hopkins, independently implicated another synapse-related protein, CNTNAP2, as an autism susceptibility gene. Since these groups converged on CNTNAP2 using different techniques, from molecular cytogenetics to genetic association studies, they essentially confirmed each others’ findings and collectively underscored its significance.
The synaptic disorder theme was furthered in late 2008 with a report from Boston Children’s Hospital that took advantage of the genetic characteristics of Middle Eastern populations. Using homozygosity mapping, an analytical technique which hadn’t yet been applied to autism, the researchers identified previously reported susceptibility genes, such as neurexin, as well as novel risk genes associated with the synapse, such as PCDH10, a gene thought to be involved in synaptic changes that underlie learning.
These convergent findings reinforce the notion that abnormalities at the synapse contribute to autism’s core symptoms. While the specific risk genes involved might differ from one individual or family to another, which helps explain some of the clinical heterogeneity, their participation in synaptic activities binds them to a common biological mechanism. Discovery of the common mechanism is what will allow us to design strategies that treat the core symptoms of autism.
Since this story was first run: Researchers continue to find connections to genes involved in synaptic function. Many of these studies have used the Autism Speaks’ AGRE cohort, including three 2009 studies published by geneticists from the University of Pennsylvania School of Medicine and The Children’s Hospital of Philadelphia. One study, published in PLoS Genetics, identified key variants in two novel genes, BZRAP1 and MDGA2, thought to be important in synaptic function and neurological development, respectively.
In honor of the anniversary of Autism Speaks’ founding on Feb 25, for the next 25 days we will be sharing stories about the many significant scientific advances that have occurred during our first five years together. Our 14th item, Autism as a Disorder of the Synapse, is from Autism Speaks’ Top 10 Autism Research Events of 2008.
