Choline Partially Prevents the Impact of Ethanol on the Lipid Raft Dependent Functions of L1 Cell Adhesion Molecule

Abstract

Background Fetal Alcohol Spectrum Disorder, the leading known cause of mental retardation, is caused by alcohol exposure during pregnancy. One mechanism of ethanol teratogenicity is the disruption of the function of L1 cell adhesion molecule (L1). These functions include enhancement of neurite outgrowth, trafficking through lipid rafts, and signal transduction. Recent data have shown that choline supplementation of rat pups reduces the effects of ethanol on neurobehavior. We sought to determine if choline could prevent the effect of ethanol on L1 function using a simple experimental system. Methods Cerebellar granule neurons (CGN) from postnatal day 6 rat pups were cultured with and without supplemental choline, and the effects on L1 signaling, lipid raft distribution and neurite outgrowth were measured in the presence or absence of ethanol. Results Choline significantly reduced the effect of ethanol on L1 signaling, the distribution of L1 in lipid rafts and L1 mediated neurite outgrowth. However, choline supplemented ethanol exposed cultures remained significantly different than controls. Conclusions Choline pretreatment of CGN significantly reduces the disruption of L1 function by ethanol, but does not completely return L1 function to baseline. This experimental system will enable discovery of the mechanism of the neuroprotective effect of choline.

Effect of Choline Supplementation on Neurological, Cognitive, and Behavioral Outcomes in Offspring Arising from Alcohol Exposure During Development: A Quantitative Systematic Review of Clinical and Preclinical Studies

“…However, choline's effects are not necessarily restricted to these brain regions. An in vitro study using cultured, neonatal rat cerebellar granule cells showed some amelioration of EtOH‐induced molecular disruption of neurite outgrowth and signal transduction by pretreatment with choline; however, these were not restored to non–EtOH‐exposed, baseline levels (Tang et al., ). Of potential concern, there were several genes that were down‐regulated ( Setdb1 , G9a , and Dnmt1 ) or up‐regulated ( Dnmt3a ) in EtOH‐exposed subjects treated with choline when compared to nonexposed controls.…”

Postnatal choline supplementation selectively attenuates hippocampal microRNA alterations associated with developmental alcohol exposure

“…In fact, pre-exposure with choline protects against ethanol-related disruptions in lipid rafts (Tang et al, 2014). So in addition to changes in gene expression and cholinergic functioning, choline can lead to long-lasting changes in cell membranes and lipid homeostasis that will ultimately affect cell survival and signaling.…”

Choline Ameliorates Deficits in Balance Caused by Acute Neonatal Ethanol Exposure

“…We have previously shown that choline supplementation of tissue culture media prior to ethanol exposure significantly ameliorates the effects of an acute ethanol exposure on L1-dependent neurite outgrowth and lipid raft- dependent signaling in cultured rat cerebellar granule neurons (30). However, previous studies on the effect of choline supplementation on rat behavior used choline supplementation with or after exposure to ethanol which did not match the experimental design of our biochemical studies (19; 20; 24-28).…”

“…In an in vitro model of cerebellar granule neurons, ethanol decreases L1 cell adhesion molecule (L1)-dependent neurite outgrowth and downstream signaling (30-32). Supplementation with choline prior to ethanol exposure shows improved neurite outgrowth and signaling in the presence of ethanol (30).…”

“…In an in vitro model of cerebellar granule neurons, ethanol decreases L1 cell adhesion molecule (L1)-dependent neurite outgrowth and downstream signaling (30-32). Supplementation with choline prior to ethanol exposure shows improved neurite outgrowth and signaling in the presence of ethanol (30). We conducted the current study to determine if choline supplementation prior to an acute exposure to ethanol on P5 would reduce the effects of ethanol on the dowel crossing test, a test of balance and coordination that relies heavily on normal cerebellar function in mice (21).…”