Williams Syndrome: A Genetic Disorder That Causes People to Be Too Friendly

Williams syndrome is a neurodevelopmental disorder characterized by hypersociability and unique neurocognitive abnormalities. One of the characteristics of Williams syndrome is an inappropriate increase in social behavior. People with the syndrome may be overly friendly, even to strangers. We performed a novel study in our lab that demonstrated that the lack of a gene called Gtf2i may play a role in Williams syndrome. When this gene is absent, there are changes to one of the most important brain components for transferring signals in the brain and are likely to contribute to the over-friendliness observed in Williams syndrome. We expose surprising mechanisms involved in an increased social behavior, which is one of the characteristics of Williams Syndrome. In this article, we demonstrate how drugs can compensate for the damaged part of the brain and can bring the increased friendly behavior down to a normal level.

Williams syndrome is a neurodevelopmental disorder characterized by hypersociability and unique neurocognitive abnormalities. One of the characteristics of Williams syndrome is an inappropriate increase in social behavior. People with the syndrome may be overly friendly, even to strangers. We performed a novel study in our lab that demonstrated that the lack of a gene called Gtf i may play a role in Williams syndrome. When this gene is absent, there are changes to one of the most important brain components for transferring signals in the brain and are likely to contribute to the over-friendliness observed in Williams syndrome. We expose surprising mechanisms involved in an increased social behavior, which is one of the characteristics of Williams Syndrome. In this article, we demonstrate how drugs can compensate for the damaged part of the brain and can bring the increased friendly behavior down to a normal level.

WHAT IS WILLIAMS SYNDROME?
Imagine walking down the street and suddenly running into a dangerous person. You would most likely be startled, cross to the other side of the street, and possibly even call the police. Well, a person with Williams syndrome would probably be so excited to see a stranger's face that he or she might not notice that the stranger is dangerous. People with Williams syndrome are described as having exceptionally friendly personalities, extremely sensitive and empathic, and therefore are also called "love children." Williams syndrome is a genetic disorder caused by the deletion of one of the two copies of about genes found on chromosome in humans [ ]. Williams syndrome's physical symptoms include problems with the heart and circulatory systems, hormonal issues, and unique facial features [ ]. The behavioral symptoms of the syndrome include over-friendliness, increased empathy (the ability to understand the feelings of others), cognitive (mental) disorders, highly developed language skills, disrupted ability to recognize danger in social situations, and high levels of non-social stress (stress that is not related to social situations).
For many years, researchers have tried to decipher the mechanism behind Williams syndrome [ , ]. Early studies found that one of the deleted genes in the syndrome, called Gtf i, was related to

Gtf i
A gene that is missing in people with Williams syndrome. The absence of Gtf i is correlated with the social disorders of the syndrome. the over-friendliness observed in Williams syndrome [ ]. But the mechanism behind this gene influences excessive friendliness was not fully understood until more recently.

THE ROLE OF THE Gtf i GENE IN WILLIAMS SYNDROME
Di erent genes are expressed in di erent types of cells, and it is possible for scientists to silence a chosen gene by erasing it from certain cells or even from the whole body. In this study, we intentionally deleted the Gtf i gene from nerve cells in the frontal brains of mice. We found that the model mice with deleted

MODEL MICE
Mice that have been genetically modified serve as a model for a certain human disease. In this case, our model mice lacked the Gtf i gene in neurons in the front of the brain.
Gtf i showed abnormal behaviors similar to those seen in Williams syndrome, including damage to the brain's structure, gentle motor skills, and increased levels of friendliness and non-social stress ( Figure ).
Through various experiments, we found a direct connection between the deletion of the Gtf i gene in mice and issues with a substance called myelin. Myelin is a fatty layer covering and insulating the signals pass through axons improperly and damage occurs in the central nervous system, leading to a functional problem, which could express for example in inadequate behaviors. This finding, which Gtf i gene deletion and its consequences. Gtf i gene deletion from nerve cells in the frontal brain of a mouse (right) causes damage similar to that seen in Williams syndrome, compared to control mice (left). The damage includes fewer oligodendrocytes, fewer axons covered in myelin and a thinner myelin layer (second row), lower neural conductivity (third row), and over-friendliness (bottom row). Adapted from Osso and Chan [ ].
shows the influence of Gtf i gene deletion on myelin, opens a new door for finding new treatments to Williams syndrome.

Gtf i Deletion in Nerve Cells in the Frontal Brain Results in Changes in Structural and Behavioral Changes
People with Williams syndrome show decreases in the volume of the brain and a thinner cortex (the outer layer of the brain). We wanted to check whether erasing the Gtf i gene from nerve cells in the frontal brain is enough to cause those structural problems. The weight of the brain and the thickness of the brain's cortex were significantly lower in month-old mice without Gtf i compared to control mice with the

CONTROL MICE
Normal, healthy mice without genetic mutations, to which the model mice are compared.

Gtf i gene.
Additionally, our model mice showed significantly higher levels of social behavior, which we evaluated using three tests. Mice without Gtf i had closer, more frequent, and longer interactions with other mice compared to control mice with the Gtf i gene. We should also mention that our model mice preferred creating more interactions with mice that were "strangers" than with an inanimate object kids.frontiersin.org December | Volume | Article | Figure   Figure The chain of processes in the brain that eventually a ects behavior. The genes in the DNA are transcribed to RNA, which is then translated into proteins. Proteins a ect the activity of brain cells, including nerve cells, therefore a ecting the way signals are sent in the brain. The way information is transferred in the brain a ects behavior.
compared to control mice. We interpreted the behavior of model mice as a preference for performing increased social behavior.
Since one of the characteristics of Williams syndrome is a high level of non-social stress, we tested the mice for behaviors related to non-social stress and found significantly higher levels of non-social stress in our model mice compared to control mice.

Gtf i Deletion A ects Myelin and Other Genes Related to Myelin
Although we deleted only the Gtf i gene in the neurons of our model mice, we found that other genes were a ected as well. We think that is because the protein made from the Gtf i gene (Figure ), called Tfii-I, is involved in regulating the expression of other genes. Surprisingly, % of the genes with lower expression in the cortex of -month-old Gtf i-deleted mice were involved in the development and function of myelin or in the development and function of oligodendrocytes,

OLIGODENDROCYTES
The cells that produce myelin.
which are the cells that produce myelin. We also found that the number of oligodendrocytes significantly decreased in the cortex of our model mice compared to control mice.
Gtf i Deletion Causes Damage in the Myelin Structure, Neural Conductivity, and Motor Skills In our model mice, we saw a significantly lower percentage of axons covered in myelin, and a significantly thinner layer of myelin on the axons, compared to control mice. This damage to the myelin layer a ects neural conductivity, which is the way signals are sent along

NEURAL CONDUCTIVITY
The way signals are sent along the axons of nerve cells. the axons of nerve cells.
Additionally, people with Williams syndrome show a decrease in fine motor skills. Our model mice also showed a lack of fine motor skills, along with weaker muscular tone in their front and rear limbs compared to control animals. This means that the damage to myelin influenced the motor skills of our model mice.

FIXING DAMAGED MYELIN AND NEURAL CONDUCTIVITY IMPROVES NEURAL AND BEHAVIORAL PROBLEMS
We saw that, as a result of the myelin damage, our model mice had problems with neural conductivity. There is a drug called -AP that is known to improve neural conductivity. We gave this drug to our model kids.frontiersin.org December | Volume | Article | mice and control mice to test whether it helped mice lacking Gtf i improve their neural conductivity and, as a result, their motor skills and social behavior. We found that a single dose of -AP improved motor skills in our model mice. Additionally, model mice showed proper social preference in the social preference test. So, we found that treatment with -AP normalized the neural conductivity, therefore improving the social behaviors and motor skills in the model mice ( Figure ).
We also wanted to test whether fixing the damaged myelin could improve the social behaviors of our model mice. To test that, we used a drug called Clemastine to -month old model mice. The Clemastine treatment normalized the number of oligodendrocytes in the cortex and increased the thickness of the myelin layer in our model mice (Figure ). We found that fixing the damage to the myelin was also su cient to fix the increased social behaviors.
Since our studies were done in mice, we wanted to test whether our findings were also valid in people with Williams syndrome. We studied brain samples of frontal brain cortex from people with Williams syndrome who donated their brains to science and compared them to samples from a control group. We found a significantly lower number of oligodendrocytes and a sharp decrease in the thickness of the myelin layer in the frontal cortices of people with Williams syndrome compared to the control group, similar to our findings in mice. We also found that % of the genes that were expressed di erently in people with Williams syndrome compared to the control group were related to myelin. Most of these genes are the same genes that were a ected in our model mice.

CONCLUSIONS
By selectively erasing Gtf i from nerve cells in mice, we found an unexpected decrease in the expression of genes related to myelin, in the number of oligodendrocytes, and in neural conductivity. We also saw similar results in tissues from humans with Williams syndrome. These data indicate that damage to myelin plays an important role in Williams syndrome, and that Gft i deletion from neurons is probably the cause of this damage. This study identifies an important role of Gft i expression in nerve cells, a crucial role for the development of oligodendrocytes and keeping proper myelin, and that the absence of these gene could contribute to some of the symptoms related to Williams syndrome.
This study sheds light on the role of myelin and neural conductivity in the inappropriate social behavior seen in Williams syndrome, and could therefore assist the development of new treatment strategies for behavioral disorders. Since the e ciency and speed of neural conductivity are dependent on myelin, dysfunctions in the features of myelin could a ect the proper communication and synchronization between di erent brain areas crucial for performing adequate behaviors. Therefore, focusing on fixing myelin dysfunctions could be an e cient treatment strategy for Williams syndrome.

ACKNOWLEDGMENTS
Noa Schuchman and Roey Shemesh, exceptional young people who worked hard to process and edit the original article to suit everyone, took part in writing this article. Noa and Roi took an active part in various projects in Dr. Boaz Barak's lab as part of the Alpha program of Tel Aviv University for Youth. Noa, , is studying chemistry and biotechnology at Ohel Shem High School in Ramat Gan. Roi, a -years-old from Petah Tikva, attends a gifted class at Ehad Ha'am High School, joined the Alpha program out of a great love for biology and the study of the human body.
Noa and Roi, we thank you from the bottom of our hearts and wish you success in the future. . doi: . /frym. .

CONFLICT OF INTEREST:
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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YOUNG REVIEWERS
ORT EBIN, SCIENCE AND TECHNOLOGY RESERVE CLASS, AGES: -We are a Science and Technological reserve class at the ORT Ebin school in Ramat Gan. ORT Ebin is a high school of sciences and arts. The school promotes leading technological subjects: biotechnology, robotics and computer science-cyber.

ELA BAR
As a child I was very curious and interested in everything. When I got to high school I studied biology, and then I was recruited to be an infantry instructor. When I arrived at university, I again chose biology, but I very quickly became interested in the brain and chose courses related to that topic. Right after completing my bachelor's degree, I started a Master's degree in the department of neurobiology. After that, I went on an interview with Dr. Barak and was very excited about the research topics in his lab, so I started my Ph.D. there. In Dr. Barak's lab, I also learned about the Alpha program, in which I help high school students conduct research projects with me in the lab. The students and I translated this paper. *elabar @gmail.com