INDIANAPOLIS — Blocking a single gene that is active in the brain could provide a means to lessen behavioral problems among children with a common genetic disease, many of whom are also diagnosed with an autism disorder, according to researchers at the Indiana University School of Medicine.
The genetic disorder, neurofibromatosis type 1, is one of the most common single-gene diseases, affecting about 1 in 3,000 children worldwide. Symptoms can range from café-au-lait spots on the skin to tumors that are disfiguring or that can press dangerously against internal organs.
“Physicians are increasingly recognizing that many children with the disorder have social and behavioral difficulties, and as many as one in five cases of autism may be associated with the same biochemical defects seen in neurofibromatosis type 1,” said Anantha Shekhar, M.D., Ph.D., Raymond E. Houk Professor of Psychiatry at the IU School of Medicine.
The researchers used a mouse model of neurofibromatosis, examining both behavioral differences from normal mice and biochemical differences in the animals’ brains, particularly in the amygdala, a brain structure associated with social behavior and emotional regulation.
Reporting their work in the journal Nature Neuroscience, the researchers found that the neurofibromatosis model mice had problems with long term social learning — remembering important social cues involving interactions with other mice. Tests also showed that neurochemical pathways between structures of the brain involved with social behavior were disrupted by the neurofibromatosis mutation.
However, blocking the activity of another gene — called Pak1, which is involved with those neurochemical pathways — improved the social behaviors of the mice. Mice bred to have both the neurofibromatosis mutation and the deletion of the Pak1 gene engaged in social behavior similar to normal mice. In addition, mice with the neurofibromatosis mutation that were injected with a compound known to block Pak1 gene activity had normal social behavior restored.
“These findings could lead to novel approaches to treating behavioral problems that are seen in NF1 patients and some patients with autism spectrum disorders,” said D. Wade Clapp, M.D., Richard L. Schreiner Professor of Pediatrics at the IU School of Medicine.
Additional researchers contributing to the study were Andrei I. Molosh, Philip L. Johnson, John P. Spence, David Arendt, Lauren M. Federici, Cristian Bernabe, Steven P. Janasik, Rajesh Khanna, Chirayu Goswami, Weiguo Zhu, Su-Jung Park and Lang Li of the IU School of Medicine; and Zaneer M. Segu and Yehia S. Mechref of the Department Chemistry, METACyt Biochemical Analysis Center at Indiana University.
The study was supported by grants from the National Center for Advanced Translational Sciences, National Institute of Mental Health, and National Cancer Institute of the U.S. National Institutes of Health (grants UL1RR025761/TR000006, R01 MH52619, MH065702, R01 CA74177-06) and an Indiana Clinical and Translational Sciences Institute predoctoral fellowship TL1 RR 025759.