Binge-like Prenatal Ethanol Exposure Causes Impaired Cellular Differentiation in the Embryonic Forebrain and Synaptic and Behavioral Defects in Adult Mice
1
Center for Dementia Research, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA
2
Molecular Imaging and Neuropathology Area, New York State Psychiatric Institute, New York, NY 10032, USA
3
Department of Psychiatry, Columbia University Irving Medical Center, New York, NY 10032, USA
4
Department of Psychiatry, New York University Langone Medical Center, New York, NY 10016, USA
*
Author to whom correspondence should be addressed.
Academic Editors: Marieta B. Heaton and Mark Burke
Brain Sci. 2022, 12(6), 793; https://doi.org/10.3390/brainsci12060793
Received: 27 April 2022
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Revised: 10 June 2022
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Accepted: 15 June 2022
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Published: 17 June 2022
(This article belongs to the Special Issue New Advances in Neurobiology and Behavioral Disturbance in Alcohol Use Disorder (AUD) including Fetal Alcohol Spectrum Disorder (FASD))
An embryo’s in-utero exposure to ethanol due to a mother’s alcohol drinking results in a range of deficits in the child that are collectively termed fetal alcohol spectrum disorders (FASDs). Prenatal ethanol exposure is one of the leading causes of preventable intellectual disability. Its neurobehavioral underpinnings warrant systematic research. We investigated the immediate effects on embryos of acute prenatal ethanol exposure during gestational days (GDs) and the influence of such exposure on persistent neurobehavioral deficits in adult offspring. We administered pregnant C57BL/6J mice with ethanol (1.75 g/kg) (GDE) or saline (GDS) intraperitoneally (i.p.) at 0 h and again at 2 h intervals on GD 8 and GD 12. Subsequently, we assessed apoptosis, differentiation, and signaling events in embryo forebrains (E13.5; GD13.5). Long-lasting effects of GDE were evaluated via a behavioral test battery. We also determined the long-term potentiation and synaptic plasticity-related protein expression in adult hippocampal tissue. GDE caused apoptosis, inhibited differentiation, and reduced pERK and pCREB signaling and the expression of transcription factors Pax6 and Lhx2. GDE caused persistent spatial and social investigation memory deficits compared with saline controls, regardless of sex. Interestingly, GDE adult mice exhibited enhanced repetitive and anxiety-like behavior, irrespective of sex. GDE reduced synaptic plasticity-related protein expression and caused hippocampal synaptic plasticity (LTP and LTD) deficits in adult offspring. These findings demonstrate that binge-like ethanol exposure at the GD8 and GD12 developmental stages causes defects in pERK–pCREB signaling and reduces the expression of Pax6 and Lhx2, leading to impaired cellular differentiation during the embryonic stage. In the adult stage, binge-like ethanol exposure caused persistent synaptic and behavioral abnormalities in adult mice. Furthermore, the findings suggest that combining ethanol exposure at two sensitive stages (GD8 and GD12) causes deficits in synaptic plasticity-associated proteins (Arc, Egr1, Fgf1, GluR1, and GluN1), leading to persistent FASD-like neurobehavioral deficits in mice.
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Keywords:
FASD; alcohol; development; brain; electrophysiology; cognition; psychiatric disorders; disabilities; synaptic plasticity; gestation; obsessive-compulsive disorder
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MDPI and ACS Style
Subbanna, S.; Basavarajappa, B.S. Binge-like Prenatal Ethanol Exposure Causes Impaired Cellular Differentiation in the Embryonic Forebrain and Synaptic and Behavioral Defects in Adult Mice. Brain Sci. 2022, 12, 793. https://doi.org/10.3390/brainsci12060793
AMA Style
Subbanna S, Basavarajappa BS. Binge-like Prenatal Ethanol Exposure Causes Impaired Cellular Differentiation in the Embryonic Forebrain and Synaptic and Behavioral Defects in Adult Mice. Brain Sciences. 2022; 12(6):793. https://doi.org/10.3390/brainsci12060793
Chicago/Turabian StyleSubbanna, Shivakumar, and Balapal S. Basavarajappa. 2022. "Binge-like Prenatal Ethanol Exposure Causes Impaired Cellular Differentiation in the Embryonic Forebrain and Synaptic and Behavioral Defects in Adult Mice" Brain Sciences 12, no. 6: 793. https://doi.org/10.3390/brainsci12060793
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