Newly Identified Pathway Links Fetal Brain Development to Adult Social Behavior

Newswise — Fetal development has been known to play an important role in social interaction, a fundamental behavior found in nearly all organisms, and later adult social behaviors. Autism, a highly heritable neurodevelopment disorder that causes difficulties with social interactions, has been postulated to be caused by neuron overgrowth in the prenatal period, although the precise timing and cause of this overgrowth has been unknown. Researchers at Case Western Reserve University School of Medicine, UCSF School of Medicine and other institutions have recently uncovered abnormalities in embryonic brain development in mice, including transient embryonic brain enlargement during neuron formation, that are responsible for abnormal adult brain structures and behavioral abnormalities. These findings demonstrate a fetal origin for social and repetitive behavior deficits, as seen in disorders such as autism.

Using engineered mice, the researchers identified a critical period during embryonic brain development for the establishment of normal social behavior and were able to link this critical period with abnormalities in specific adult brain structures. After identifying these abnormalities, the researchers were then able to intervene and treat mice during fetal development. The embryonically treated mice progressed without adult behavioral deficits. Further studies will be required to determine the consequences of abnormal development of cortical neurons on adult brain circuitry and function, as well as possible therapeutic interventions. The results of the study were published in the current issue of Molecular Psychiatry.

“It is likely that abnormal brain development can cause long term alterations in brain circuitry that may later manifest as behavioral affective disorders in adults. By defining the pathway that connects embryonic development to adult social conditions, we were able to target the pathway in the embryo and provide a potential approach to stop the later development of abnormal behaviors. In the mice we treated, we were able to reverse the embryonic deficits that appear to lead to social and repetitive behavior disorders,” said Anthony Wynshaw-Boris, MD, PhD, Chair, Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine and University Hospitals Case Medical Center. The work was initiated when he was a professor in the Department of Pediatrics at UCSF School of Medicine.

“We examined brains from the mouse embryos that developed social and repetitive behavioral abnormalities as adults since a number of children that develop autism display larger brains sooner after birth than typically developing children,” said Haim Belinson, PhD, a postdoctoral fellow in the Wynshaw-Boris laboratory and first author of the Molecular Psychiatry paper. “We believe these findings may be relevant to the development of autism, and we are currently investigating this further.”

This research was supported by NINDS grants R01NS073159 (AWB) and R01NS079231 (RYB & NA), the Simons Foundation SFARI #256769 (NA), the Ontario Brain Institute (JPL), and an Autism Speaks Translational Postdoctoral Fellowship #7587 (HB). Behavioral data were obtained with the help of the Gladstone Institute Behavioral Core (supported by NIH grant P30NS065780). This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging.

Complete author list:• H. Belinson, J. Nakatani, BA. Babineau and M. Bershteyn, Department of Pediatrics, Institute for Human Genetics, Edyth and Eli Broad Institute of Regenerative Medicine, University of California, San-Francisco School of Medicine, San Francisco, CA USA• RY. Birnbaum, Department of Life Sciences, Ben-Gurion University at the Negev, Beer-Sheva, Israel• J. Ellegood, Mouse Imaging Centre, Hospital for Sick Children, Toronto, Ontario, Canada; • RJ. McEvilly and GM. Rosenfeld, Howard Hughes Medical Institute, Department and School of Medicine, University of California, San Diego• JM. Long, Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institute of Health, Baltimore, MD USA• K. Willert, Department of Cell and Molecular Biology, Institute for Regenerative Medicine, University of California, San Diego School of Medicine La Jolla, CA USA• OD. Klein, Department of Orofacial Sciences and Program in Craniofacial and Mesenchymal Biology, University of California San Francisco, San Francisco, CA USA• N. Ahituv, Department of Bioengineering and Therapeutic Sciences, Institute for Human Genetics, University of California San Francisco; San-Francisco, CA USA• JP. Lerch, Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. And Mouse Imaging Centre, Hospital for Sick Children, Toronto, Ontario, Canada• A. Wynshaw-Boris, Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA and Department of Pediatrics, Institute for Human Genetics, Edyth and Eli Broad Institute of Regenerative Medicine, University of California, San-Francisco School of Medicine, San Francisco, CA USA (corresponding author)

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About AutismAutism and autism spectrum disorder (ASD) refer to a group of complex neurodevelopment disorders characterized by repetitive and characteristic patterns of behavior and difficulties with social communication and interaction. The U.S. Centers for Disease Control and Prevention (CDC) estimates that about 1 in 68 children has been diagnosed with ASD.

About Case Western Reserve University School of MedicineFounded in 1843, Case Western Reserve University School of Medicine is the largest medical research institution in Ohio and is among the nation’s top medical schools for research funding from the National Institutes of Health. The School of Medicine is recognized throughout the international medical community for outstanding achievements in teaching. The School’s innovative and pioneering Western Reserve2 curriculum interweaves four themes--research and scholarship, clinical mastery, leadership, and civic professionalism—to prepare students for the practice of evidence-based medicine in the rapidly changing health care environment of the 21st century. Nine Nobel Laureates have been affiliated with the School of Medicine. Annually, the School of Medicine trains more than 800 MD and MD/PhD students and ranks in the top 25 among U.S. research-oriented medical schools as designated by U.S. News & World Report’s “Guide to Graduate Education.” The School of Medicine’s primary affiliate is University Hospitals Case Medical Center and is additionally affiliated with MetroHealth Medical Center, the Louis Stokes Cleveland Department of Veterans Affairs Medical Center, and the Cleveland Clinic, with which it established the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University in 2002. www.case.edu/medicine.