biostudies-literatureHwang HMNICHD NIH HHSFoundation for the National Institutes of HealthFoundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)Texas A&M University’s Accountability, Climate, Equity, and Scholarship (ACES) Faculty Fellows ProgramDistrict of Columbia Intellectual and Developmental Disabilities Research Center (DC-IDDRC) Award programNIAAA NIH HHSLilly Endowment3364-3380https://www.ebi.ac.uk/biostudies/studies/S-EPMC11541007biostudies-literatureUnknown29(11)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.Molecular psychiatryReduction of APOE accounts for neurobehavioral deficits in fetal alcohol spectrum disorders.PMC11541007U24AA030169U01AA025103U01AA014809U01 AA021886R01 AA026272R01AA026272P50HD105328P50 HD105328F31 AA027693R01AA025215U01 AA014809F31AA027693U01 AA026103R01 AA025215U24 AA030169U01 AA014834U01AA014834U01 AA014835U01AA014835Sasaki JWetherill LYamashita CMahnke AHChambers CHwang HMAbreu MForoud TTorii MMatsumoto YIto MEdwards AMattson SNSchwantes-An THYamashita SMohammad SHashimoto-Torii KDutta DJMiranda RCfalseReduction of APOE accounts for neurobehavioral deficits in fetal alcohol spectrum disorders.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.2024-01-01T00:00:00Z2024 Nov2026-06-01T16:22:57.401Z2025-04-04T11:42:32.426ZS-EPMC115410073873484410.1038/s41380-024-02586-6