An international team led by Case Western Reserve researchers has discovered a way to treat abnormalities in fetal brain development in mice that eliminates the animals’ symptoms of neurological disorders in adulthood.

The study, which began when two of the key researchers now at Case Western Reserve were at the University of California at San Francisco, could have significant implications for prenatal interventions to prevent behavioral deficits seen in conditions such as autism. The findings appeared in Molecular Psychiatry.

The scientists will conduct further research to elucidate the implications of abnormalities in cortical neuron development on adult brain circuitry and function. In addition, they will explore options for therapeutic interventions.

Nevertheless, this work itself marks a critical breakthrough in clarifying the timing and nature of the formation of the social neural circuit, both of which had been poorly understood.

“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,” said Anthony Wynshaw-Boris, chair of the medical school’s Department of Genetics and Genome Sciences. “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”.

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. Using engineered mice, Wynshaw-Boris and his colleagues identified a critical period during embryonic brain development for the establishment of normal social behavior. From there they linked the critical period with abnormalities in specific adult brain structures.

“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, 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:

  • 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
  • Birnbaum, Department of Life Sciences, Ben-Gurion University at the Negev, Beer-Sheva, Israel
  • Ellegood, Mouse Imaging Centre, Hospital for Sick Children, Toronto
  • McEvilly and GM. Rosenfeld, Howard Hughes Medical Institute, Department and School of Medicine, University of California, San Diego
  • Long, Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institute of Health, Baltimore
  • Willert, Department of Cell and Molecular Biology, Institute for Regenerative Medicine, University of California, San Diego School of Medicine La Jolla, Calif.
  • Klein, Department of Orofacial Sciences and Program in Craniofacial and Mesenchymal Biology, University of California San Francisco
  • Ahituv, Department of Bioengineering and Therapeutic Sciences, Institute for Human Genetics, University of California San Francisco
  • Lerch, Department of Medical Biophysics, University of Toronto, and Mouse Imaging Centre, Hospital for Sick Children, Toronto
  • Wynshaw-Boris, Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine and Department of Pediatrics, Institute for Human Genetics, Edyth and Eli Broad Institute of Regenerative Medicine, University of California, San Francisco School of Medicine (corresponding author)