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That same year, another set of mutations in autism came to light, causing excitement because they, too, pointed to components of the synapse-making machinery. In the 1990s, Thomas Südhof, an HHMI investigator at University of Texas Southwestern Medical Center at Dallas, identified genes for two key families of proteins involved in creating the brain's synaptic nerve connections.
The two gene-protein families, called neurexins and neuroligins, are located on opposite sides of the “cleft” or tiny space where the neurons meet at a synapse. These two protein complexes extend out of the nerve cells and physically bridge the synaptic divide, but they also affect the excitatory-inhibitory balance of nerve signal traffic.
Thomas Bourgeron at the Pasteur Institute in Paris first reported mutations affecting these proteins in autistic patients in 2003. He found that two pairs of Swedish brothers with autism disorders had mutations in the neuroligin proteins that Südhof had identified seven years earlier.
More recently, a larger international study revealed a gene for one of the neurexins in a chromosomal region linked to autism. Bourgeron has also found mutations in another gene expressed in synapses, Shank3, which interacts with neuroligins. Other scientists have uncovered evidence that links the gene with autism.
“I suspect that Shank3 is one of at least a dozen genes that have rare variants in them which likely are causative for the disease,” comments Louis Kunkel, an HHMI investigator at Children's Hospital Boston, who is hunting for autism genes. “These will all likely be important in neuronal maturation and learning.”
Another piece of the synaptic puzzle recently emerged from the lab of HHMI investigator Li-Huei Tsai at the Picower Institute for Learning and Memory at MIT. Publishing in Neuron in 2007, she reported that a protein, Cdk5, modifies another protein called CASK and promotes the interaction of CASK with neurexin proteins at newly forming synapses.
“This general process seems to be extremely relevant to autism,” Tsai says, “because a lot of the proteins implicated in autism spectrum disorders all seem to overlap in this particular area of synapse development.”
A dramatic demonstration of how a single mutation can cause autistic symptoms came when Südhof created lab mice containing the neuroligin-3 gene mutation previously found in humans. The mutation lowered the amount of neuroligin-3 protein in the animals' forebrains by 90 percent, with a surprising consequence for their behavior.
Compared with control mice, the gene-altered rodents were less social: they spent less time interacting with a new mouse placed in their cage. But they became smarter: they took fewer days to learn the location of a platform submerged in murky water, indicating enhanced spatial memory.
“This is incredibly exciting,” Südhof says. “Usually when you impair mouse cognitive function, they're just stupid. These mice are not stupid—they have a huge positive change in learning along with a modest social deficit. This is the first genetic dissection of circuits that underlie these different effects.”
The events leading from mutation to altered behavior aren't fully understood, Südhof says, but the results “validate the whole idea that autism is related to synapses.”
Further progress in autism research means continuing the gene hunt on a broad front, deploying a variety of strategies. Many different kinds of genetic flaws appear to be involved—mutations, deletions, copy number variations (too many or too few copies of critical genes), large and small chromosome effects. Fortunately, new genomic tools such as single nucleotide polymorphism “chips” can spot increasingly small genetic flaws.
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