Reduction of APOE accounts for neurobehavioral deficits in fetal alcohol spectrum disorders

Hye M. Hwang, Center for Neuroscience Research, The Children's Research Institute, Children's National Hospital, Washington, DC, USA.
Satoshi Yamashita, Center for Neuroscience Research, The Children's Research Institute, Children's National Hospital, Washington, DC, USA.
Yu Matsumoto, Center for Neuroscience Research, The Children's Research Institute, Children's National Hospital, Washington, DC, USA.
Mariko Ito, Center for Neuroscience Research, The Children's Research Institute, Children's National Hospital, Washington, DC, USA.
Alex Edwards, Center for Neuroscience Research, The Children's Research Institute, Children's National Hospital, Washington, DC, USA.
Junko Sasaki, Center for Neuroscience Research, The Children's Research Institute, Children's National Hospital, Washington, DC, USA.
Dipankar J. Dutta, Center for Neuroscience Research, The Children's Research Institute, Children's National Hospital, Washington, DC, USA.
Shahid Mohammad, Center for Neuroscience Research, The Children's Research Institute, Children's National Hospital, Washington, DC, USA.
Chiho Yamashita, Center for Neuroscience Research, The Children's Research Institute, Children's National Hospital, Washington, DC, USA.
Leah Wetherill, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
Tae-Hwi Schwantes-An, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
Marco Abreu, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
Amanda H. Mahnke, Department of Neuroscience and Experimental Therapeutics, Texas A&M University School of Medicine, Bryan, TX, USA.
Sarah N. Mattson, Center for Behavioral Teratology, San Diego State University, San Diego, CA, USA.
Tatiana Foroud, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
Rajesh C. Miranda, Department of Neuroscience and Experimental Therapeutics, Texas A&M University School of Medicine, Bryan, TX, USA.
Christina Chambers, Department of Pediatrics, University of California San Diego, San Diego, CA, USA.
Masaaki Torii, Center for Neuroscience Research, The Children's Research Institute, Children's National Hospital, Washington, DC, USA. mtorii@childrensnational.org.
Kazue Hashimoto-Torii, Center for Neuroscience Research, The Children's Research Institute, Children's National Hospital, Washington, DC, USA. khtorii@childrensnational.org.

Document Type

Journal Article

Publication Date

5-11-2024

Journal

Molecular psychiatry

DOI

10.1038/s41380-024-02586-6

Abstract

A hallmark of fetal alcohol spectrum disorders (FASD) is neurobehavioral deficits that still do not have effective treatment. Here, we present that reduction of Apolipoprotein E (APOE) is critically involved in neurobehavioral deficits in FASD. We show that prenatal alcohol exposure (PAE) changes chromatin accessibility of Apoe locus, and causes reduction of APOE levels in both the brain and peripheral blood in postnatal mice. Of note, postnatal administration of an APOE receptor agonist (APOE-RA) mitigates motor learning deficits and anxiety in those mice. Several molecular and electrophysiological properties essential for learning, which are altered by PAE, are restored by APOE-RA. Our human genome-wide association study further reveals that the interaction of PAE and a single nucleotide polymorphism in the APOE enhancer which chromatin is closed by PAE in mice is associated with lower scores in the delayed matching-to-sample task in children. APOE in the plasma is also reduced in PAE children, and the reduced level is associated with their lower cognitive performance. These findings suggest that controlling the APOE level can serve as an effective treatment for neurobehavioral deficits in FASD.

Department

Pediatrics

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