Postnatal Choline Supplementation Ameliorates Synaptic Plasticity Deficits Following Prenatal Ethanol Exposure in a Sex-Specific Manner
Date
2023-07-13
Authors
Gräfe, Erin
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Abstract
Background: Fetal Alcohol Spectrum Disorder (FASD) is one of the leading causes of neurodevelopmental impairment. FASD is the diagnostic term to encompass the range of physical, cognitive, or emotional impairments due to prenatal ethanol exposure (PNEE). One of the most notable consequences of PNEE are deficits in hippocampal synaptic plasticity, and consequently, learning and memory impairments. Currently, there is no treatment for FASD. However, there are promising data to demonstrate that the essential nutrient choline may improve outcomes following developmental ethanol exposure. Questions remain as to how postnatal choline supplementation improves hippocampal outcomes at a synaptic level, whether these occur in a sex-dependent manner, and if any changes will persist into adulthood.
Methods: This dissertation employed a first-two trimester moderate model of PNEE (Gestational day 1-22). Offspring were supplemented with choline chloride (100 mg/kg/day) from postnatal day (PND) 10-30, then tested either immediately following treatment (PND 31-36) or in adulthood (PND 60-90). In juvenile offspring bidirectional plasticity was evaluated, as well as behavioural changes using the Radial Arm Maze. In adulthood, saturating and subthreshold long-term potentiation (LTP) was evaluated, as well as alterations in GluN2B functionality.
Results: PNEE reduced the magnitude of LTP in male juvenile offspring, but not in females. Choline treatment increased LTP in both male and female PNEE offspring. However, choline treatment insignificantly decreased the amount of long-term depression (LTD) in male offspring, regardless of prenatal environment. Improvements in PNEE male LTP did not translate to behavioural improvements in the Radial Arm Maze, either in the working or reference memory performance. Female juvenile offspring did not learn the task over the course of the five trials and this lack of learning was not due to differences in search strategy. In adulthood, there were no evident changes in LTP with PNEE or with choline treatment in either sex. Despite the lack of deficit or improvement, choline treatment altered the LTP threshold, such that lower frequency stimulating protocols still resulted in LTP in choline treated offspring. While it is not clear why this change in LTP threshold occurred, it could be due to alterations in GluN2B functionality; GluN2B antagonism increased field excitatory postsynaptic potential (fEPSP) size in control offspring, but not in saline treated PNEE adults.
Conclusion & Significance: This dissertation demonstrated that postnatal choline supplementation ameliorated the deficits in LTP in PNEE males and further increased LTP in PNEE females. However, these changes in synaptic plasticity did not persist in adulthood when using a saturating conditioning stimulus. There may still be alterations in hippocampal LTP threshold after treatment cessation, but the exact locus of action remains to be uncovered. These data further support choline as a treatment for PNEE, but also suggest that extended choline treatment may produce more long-lasting changes.
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Keywords
Prenatal Ethanol, Fetal Alcohol Spectrum Disorder, Choline, Synaptic Plasticity, Hippocampus, Sex Differences