Williams syndrome, a rare neurodegenerative disease that affects about one in 10,000 babies born in the United States, produces a number of symptoms including cognitive impairment, cardiovascular problems and extremely friendly or hypersensitivity.
In a mouse study, MIT neurologists have gathered a new look at the molecular mechanisms underlying this hypersensitivity. They found that the loss of one of the genes associated with Williams syndrome resulted in a thinning of the fat layer that isolated the neurons and helped them carry electrical signals in the brain.
Researchers have also shown that they can overturn symptoms by increasing the production of this coating, known as myelin. This is important because, although Williams syndrome is rare, many other neurological disorders and neurological conditions are associated with myelinizable deficits, "said Guowing Feng, James White and Patricia Poatras, a professor of neuroscience at the McGovern Institute for Brain Research.
"The significance is not only for Williams syndrome," says Feng, one of the senior authors of the study. "In other neurological diseases, especially in some of the autistic spectrum disorders, this may be a new direction to address, not only the pathology but also the potential treatments."
Gigang He, a professor of neurology and ophthalmology at Harvard Medical School, is also the senior author of the report, which appeared in the April 22 issue. Nature Neuroscience, Former MIT post-director Boaz Barak, who is currently a senior researcher at Tel Aviv University in Israel, is the lead author and lead author of the report.
Williams syndrome, caused by the loss of one of the two copies of a segment of chromosome 7, can cause learning disabilities, especially for tasks that require visual and motor skills, such as solving a puzzle. Some people with this disorder also show poor concentration and hyperactivity and are more likely to experience phobias.
In this study, researchers decided to focus on one of the 25 genes in this segment, known as Gtf2i. Based on studies of patients with fewer deleted genes, scientists linked the Gtf2i gene to the hyperacidity seen in Williams syndrome.
Working with a mouse model, the researchers figured out a way to destroy the gene specifically from excitatory neurons in the anterior brain, including the cortex, hippocampus and amygdala (a region important to the treatment of emotions). They found that these mice showed elevated levels of social behavior as measured by how long they spend interacting with other mice. Mice also show a deficiency of fine motor skills and increased unsocial related anxiety, which are also symptoms of Williams syndrome.
The researchers then sequenced RNA from the bark of the mice to see which genes are affected by the loss of Gtf2i. Gtf2i encodes a transcription factor so it controls the expression of many other genes. Researchers have found that about 70% of genes with significantly reduced levels of expression are involved in the process of myelination.
"Myelin is the insulating layer that envelops the axons that extend from the neuronal cell bodies," Barak says. "When they do not have the right properties, it will lead to faster or slower transduction of an electrical signal that affects the synchronization of brain activity."
Additional studies have shown that mice have only about half the normal number of mature oligodendrocytes – the brain cells that produce myelin. However, the number of oligodendrocyte precursor cells is normal, so the researchers suspect that the maturation and differentiation processes of these cells are somehow disrupted when Gtf2i lacks in the neurons.
This is surprising because Gtf2i is not extracted from oligodendrocytes or their precursors. Thus, destruction of the gene in neurons may in some way affect the process of maturation of oligodendrocytes, the researchers suggest. It is not yet known how this interaction can work.
"This is an issue we are interested in, but we do not know whether it is a secretive factor or any other kind of signal or activity," Feng said.
In addition, researchers found that myelin around the axons of the front brain is significantly thinner than normal mice. In addition, the electrical signals are smaller and take longer to pass the brain in mice lacking Gtf2i.
Reversal of symptoms
It remains to be discovered exactly how this reduction in myelination leads to hypersensitivity. Researchers suspect that myelin deficiency affects brain circles that normally suppress social behavior, making mice more eager to interact with others.
"This is probably the explanation, but exactly which chains and how it works, we still do not know," says Feng.
Researchers also found that they can reverse the symptoms by treating mice with medications that improve myelination. One of these drugs, approved by the FDA antihistamine, called clemastine fumarate, is now in clinical trials for the treatment of multiple sclerosis that affects the myelinization of neurons in the brain and spinal cord. Researchers believe it would be useful to test these drugs in Williams syndrome patients because they found a thinner myelin and a reduced number of mature oligodendrocytes in brain samples from people who had Williams syndrome compared to typical human brain samples.
"Mice are not humans, but the pathology is similar in this case, which means that it can be translated," says Feng. – It may be that these patients, if you improve their myelination early, can at least improve some of the conditions. This is our hope.
Such drugs are likely to help primarily the social and subtle motor problems caused by Williams syndrome, not the symptoms that come from the deletion of other genes, the researchers said. They can also help treat other diseases, such as autism spectrum disorders, in which myelination is sometimes impaired, Feng said.
"We believe that this can be widened in autism and other neurological disorders." For these conditions, improved myelination can be a major factor in treatment, "he says. "We are now examining other animal models of neurological disorders to see if they have myelinemic defects and whether improved myelination can improve some of the pathologies of the defects."
The study is funded by the Simons Foundation, the Poetras Affective Disorder Research Center at the MTI, the Stanley Center for Psychiatric Research at the Institute of Massachusetts Institute of Technology and Harvard, and Simson's Center for Social Brain at MIT.