These are fMRI brain activations in typical people (neurotypical, NT) and Asperger patients (AS) thinking about how words that describe traits (such as kind, smart, or lazy) apply to themselves, and whether the words are generally positive or negative. The control subjects engage a brain system known to be involved in self-reflection more powerfully than the AS people do. The bottom row of images quantifies this difference by directly comparing the activations of NT and AS participants. Warm colors in this image indicate areas of the brain activated more by the self-reflecting NT people than by self-reflecting AS patients.
Since Rett syndrome is caused by mutations to a single gene, researchers hope to cure it by overcoming the effects of that mutation. Sur appears to have found a promising tactic: in February 2009, he reported that a protein called IGF-1, an insulin-like growth factor that regulates development of nerve cells, spurs synapses to mature, reversing Rett symptoms in infant mice. Sur zeroed in on IGF-1 as a potential treatment after earlier work in his lab showed that it helps promote synapse growth. Clinical trials are expected to start this year in patients 2 to 12 years old. “Earlier is better,” he says, “but we believe the adolescent and even adult brain has potential for recovery of function in certain disorders of brain development.”
Those trials will join a handful already under way for the potential Fragile X treatment discovered by Bear. Fragile X, which causes learning disabilities as well as autism symptoms, is the most common inherited cause of mental impairment, affecting about one in 8,000 girls and one in 4,000 boys.
Children with Fragile X have a mutation in a gene that encodes FMRP (Fragile X mental retardation protein), a protein needed for normal brain development. An international team of researchers discovered the mutation in 1991, but they weren’t sure of the missing protein’s role in the brain. Later that decade, they discovered that it was often associated with a molecule Bear had been studying for years: the metabotropic glutamate receptor 5 (mGluR5).
Bear (then a professor at Brown University) knew that mGluR5 was involved in the neurophysiological phenomenon known as long-term depression (LTD), a suppression of synapses that’s part of the system the brain uses to fine-tune connections by weakening or strengthening them as needed. At first, he hypothesized that Fragile X protein was necessary for LTD: activating mGLuR5, he thought, would stimulate production of the protein and stifle unwanted synapse growth. He tested the theory by studying genetically engineered mice that cannot produce FMRP and thus display symptoms like those of Fragile X, including impaired learning ability, enlarged testicles, hypersensitivity to sensory stimuli, and increased susceptibility to seizures. To his astonishment, the mice showed exaggerated LTD–the opposite of what he expected.
The results were so strange that his team delayed publication to do experiments over and over, says Bear, who came to MIT in 2003. “We just had this orphan result which essentially got shelved for a while,” he recalls. Suddenly it occurred to him that maybe mGluR5 activates the process necessary for LTD and FMRP restrains it, preventing synapse development from being suppressed too much. That led Bear to wonder whether blocking mGluR5 could compensate for a shortage of FMRP, effectively restoring balance to synapse development and reversing Fragile X.
Bear admits to being “pretty nervous” the first time he went to a conference of Fragile X researchers to present the theory, in 2000. “It frankly seemed absurd to think you could correct a disorder as varied as Fragile X by this one mechanism,” he says. “I remember being relieved when I didn’t get laughed at.” But in 2007, Bear and his colleagues showed that halving the number of metabotropic glutamate receptors in mice with Fragile X symptoms does indeed reverse those symptoms.
Though research like Bear’s and Sur’s targets types of autism caused by single-gene defects, “the bottom line is that synaptic dysfunction is fairly common across multiple forms of autism,” Sur says. He hopes the drugs that researchers develop to target specific genetic problems with brain signaling can also treat other forms of autism that involve similar cellular malfunctions.