To many people, intellectual disability and developmental delay are synonymous. The Latin root of "retarded," in fact, means to delay, or slow down.

But in findings published this week, scientists have shown that sometimes the opposite can be the case. Gavin Rumbaugh told BioWorld Today that in mice lacking one copy of the gene SYNGAP1, which are an animal model for severe mental retardation, "what we found is that the circuits appear to develop much faster."

Rumbaugh, who is at the Scripps Research Institute's Florida campus, thinks that such fast development ultimately leads to reduced plasticity during the periods when experience normally fine-tunes such circuits.

Mutations in SynGAP1 account for around 1 percent of intellectual disability. The gene is unusual in several ways. For one thing, disruptions of the gene lead very specifically to intellectual disability.

Most cognitive disabilities are part of a larger syndrome such as Down syndrome, which comes with a host of physical symptoms, from the typical upward slant and epicanthal fold of the eyes to a strong predisposition toward Alzheimer's disease in midlife.

SynGAP1 mutations affect cognitive abilities only. Individuals with such mutations, Rumbaugh said, are "normal in every other way." But they have severe cognitive disabilities. Their IQ is usually less than 50 – a level of disability that leaves them unable to even speak. "Most of them are institutionalized because they need constant care," he said.

Also, though risk factors for intellectual disability and autism spectrum disorders – which are often accompanied by intellectual disability – abound, SynGAP1 mutations are both directly causative and highly predictive of disease. "If you get one of these mutations, you will have intellectual disabilities," Rumbaugh said.

The specificity of SynGAP 1's effects is reflected in the specificity of its expression. "It is only expressed in the brain, and it's only expressed in neurons, and it only lives in one small part of the neuron – the synapse," Rumbaugh said.

Another way in which the protein is unusual is that the loss of only one copy of the protein leads to severe disability. Oftentimes, when one copy of a gene is defective, cells can more or less get by on the half of the cell's protein that is produced by the other copy. But SynGAP1 works by shutting off pro-growth G-protein signaling, and "apparently you need all of your SynGAP1, because otherwise you don't have enough stop signal."

In the experiments described in their paper, which appeared in the Nov. 9, 2012, issue of Cell, senior author Rumbaugh and his team showed that in mice lacking one copy of the SynGAP1, connections between neurons matured earlier in development than in animals with both copies. That, in turn, led to great excitability in brain regions that are important for memory and cognition, as well as learning deficits and abnormal social behaviors.

The authors then made a conditional knockout to test whether such abnormalities could be reversed in older animals if gene expression was restored. They found that SynGAP1 expression is necessary during development – knocking out the gene in adult animals had little to no effect. But once it was missing during that critical time period, later restoration of gene expression did not improve the animals' symptoms.

Rumbaugh and his team are currently working out the exact time frame that SynGAP1 is necessary for brain development to occur normally.

"Once you know that window," he said, "you can start testing therapies."

As to what such therapies might be, on the one hand, the team's findings provide a sobering perspective on recent work that has suggested that some neurodevelopmental disorders, including both Rett syndrome and Fragile X syndrome, may remain reversible long after their symptoms are established. (See BioWorld Today, April 12, 2012.)

Some mouse models are showing improvement in adult mice, and this is great for a lot of people," Rumbaugh said. "But almost all of this work is being done in two or three mouse models. . . . We think that it's probably not the case [that symptoms can be reversed in adulthood] for the majority, because these models are not representative."

He estimated that there are up to 400,000 individuals in the U.S. who are disabled due to SynGAP1 mutations, which puts its prevalence "into the same ballpark as Fragile X syndrome."

Though the research now published in Cell suggested that individuals whose mental retardation is due to SynGAP1 mutations will not be cured in adulthood, Rumbaugh stressed that they still suggest such individuals can be treated – if they are diagnosed early enough. Clearly, identifying a baby or fetus with a SynGAP1 mutation at or before birth is more challenging than treating an older child or even adult once symptoms have emerged. But the necessary technology is available. "Just in the past year, in utero sequencing of fetal DNA has become a reality," Rumbaugh said. And like all sequencing, it is cheap and becoming cheaper.

If prenatal or peripartum diagnostics become realistic, such children could be treated in time to make a difference, whether via gene therapy or drugs to boost the protein's activity, or the expression of the remaining SynGAP1 allele. "If you were able to do this," Rumbaugh said, "you might be able to completely reverse these effects."