Vaishnavi Sukumar

Background:  Fetal alcohol syndrome is a disorder caused by the consumption of ethanol by a child bearing mother during the gestation period and can have a spectrum of effects on the fetus once they are born. It is reported that around 40,000 babies are diagnosed with fetal alcohol syndrome yearly in the United States.¹ Fetal alcohol syndrome affects cognitive, behavioral, and memory functions which is mainly seen due to the effects of ethanol on the hippocampus.⁶ Ethanol passes the placenta and reaches the fetus causing changes in metabolic pathways due to epigenetic modifications, apoptosis, and changes in gene expression.⁶ Ethanol affects the process of gastrulation and neural crest migration. The underlying mechanism that is seen to affect the fetus’ hippocampus is based on the effects of ethanol on GABAergic interneurons and GABAergic signaling.

Objective:  In this narrative review, we explored what mechanisms, specifically the GABAergic and some details including the glutamatergic pathways, that are affected by ethanol and the ways that these mechanisms are disturbed.

Search Methods:  An online search in the PubMed Database was conducted from the years 2017-2023 using the following keywords, “Fetal Alcohol Syndrome”, “GABA”, “Glutamate”, “Hippocampus”, and “apoptosis.”

Results:  Studies indicated that mice that were injected with alcohol revealed that exposure to alcohol during the critical period of fetal development can alter hippocampal dependent behaviors in mice, leading to long lasting behavior deficits.⁶ There is decreased expression of genes related to neuronal development and synaptic function once the mice were exposed to ethanol.⁴ The main signaling pathway affected was GABAergic signaling. In a study conducted using a rat model of moderate prenatal alcohol exposed rats, finding showed a decrease in parvalbumin- expressing GABAergic interneurons in rats exposed to moderate levels of prenatal alcohol.⁴ This reduction has an impact on inhibitory control and excitability of the hippocampus leading to an imbalance in inhibitory-excitatory circuitry. GABA is an important neurotransmitter that helps the brain undergo neurulation. In the CA1 region of the hippocampus there is a reduction in the number of GABAergic interneurons and parvalbumin GABAergic interneurons.⁴ There is also evidence that another mechanism of hippocampal degeneration seen in FASD is apoptosis of GABAergic interneurons in the hippocampus. In this study there was an increase in caspase-3 activity which is a molecule that drives apoptosis and the areas affected were mostly the hilus, CA1, CA3, and GCL regions.³ There was also a decrease in dendritic spines in the hippocampus of the mice that were observed.³

Conclusion:  Ethanol exposure during development can cause significant changes to the hippocampus’ GABAergic pathways. There are currently no specific treatments but there are interventions that may help mitigate some of the effects of ethanol exposure on the developing brain. One potential approach is to target GABA receptors or increase GABA levels in the brian. More research is needed to better understand the mechanisms of hippocampal degeneration and to develop more effective treatments for FASD.

Works Cited:

1. Mira RG, Lira M, Tapia-Rojas C, Rebolledo DL, Quintanilla RA, Cerpa W. Effect ofAlcohol on Hippocampal-Dependent Plasticity and Behavior: Role of Glutamatergic Synaptic Transmission. Front Behav Neurosci. 2020;13:288. Published 2020 Jan 24. doi:10.3389/fnbeh.2019.00288
2. Fish EW, Wieczorek LA, Rumple A, et al. The enduring impact of neurulation stage alcohol exposure: A combined behavioral and structural neuroimaging study in adult male and female C57BL/6J mice. Behav Brain Res. 2018;338:173-184. doi:10.1016/j.bbr.2017.10.020
3. Bird CW, Taylor DH, Pinkowski NJ, Chavez GJ, Valenzuela CF. Long-term Reductions in the Population of GABAergic Interneurons in the Mouse Hippocampus following Developmental Ethanol Exposure. Neuroscience. 2018;383:60-73. doi:10.1016/j.neuroscience.2018.05.003
4. Madden JT, Thompson SM, Magcalas CM, Wagner JL, Hamilton DA, Savage DD, Clark BJ, Pentkowski NS. Moderate prenatal alcohol exposure reduces parvalbumin expressing GABAergic interneurons in the dorsal hippocampus of adult male and female rat offspring. Alcohol. 2018 Feb;66:1-8. doi: 10.1016/j.alcohol.2017.04.002. PMID: 29306746.
5. Wilhoit LF, Scott DA, Simecka BA. Fetal Alcohol Spectrum Disorders: Characteristics, Complications, and Treatment. Community mental health journal. 2017;53(6):711-718. doi:10.1007/s10597-017-0104-0
6. Gomez D, Abdul-Rahman O. Fetal alcohol spectrum disorders: current state of diagnosis and treatment. Current Opinion in Pediatrics. 2021; 33 (6): 570-575. doi: 10.1097/MOP.0000000000001071.
7. Lotfullina N, Khazipov R. Ethanol and the Developing Brain: Inhibition of Neuronal Activity and Neuroapoptosis. The Neuroscientist. 2018;24(2):130-141. doi:10.1177/107385841771266