Chronic Binge Alcohol Exposure During Pregnancy Alters mTOR System in Rat Fetal Hippocampus

Abstract

Background: Gestational alcohol exposure can contribute to fetal alcohol spectrum disorders (FASD), an array of cognitive, behavioral, and physical developmental impairments. Mammalian target of rapamycin (mTOR) plays a key role in regulating protein synthesis in response to neuronal activity, thereby modulating synaptic plasticity and long-term memory formation in the brain. Based on our previous quantitative mass spectrometry proteomic studies, we hypothesized that gestational chronic binge alcohol exposure alters mTOR signaling and downstream pathways in the fetal hippocampus.Methods: Pregnant Sprague-Dawley rats were assigned to either a pair-fed control (PF-Cont) or a binge alcohol (Alcohol) treatment group. Alcohol dams were acclimatized via a once-daily orogastric gavage of 4.5 g/kg alcohol (peak BAC, 216 mg/dl) from GD 5-10 and progressed to 6 g/kg alcohol (peak BAC, 289 mg/dl) from GD 11-21. Pair-fed dams similarly received isocaloric maltose dextrin.Results: In the Alcohol group, following this exposure paradigm, fetal body weight and crownrump length were decreased. The phosphorylation level of mTOR (P-mTOR) in the fetal hippocampus was decreased in the Alcohol group compared with controls. Alcohol exposure resulted in dysregulation of fetal hippocampal mTORC1 signaling, as evidenced by an increase in total 4E-BP1 expression. Phosphorylation levels of 4E-BP1 and p70 S6K were also increased following alcohol exposure. P-mTOR and P-4E-BP1 were exclusively detected in the dentate gyrus and oriens layer of the fetal hippocampus, respectively. DEPTOR and RICTOR expression levels in the fetal hippocampus were increased; however, RAPTOR was not altered by chronic binge alcohol exposure.Conclusion: We conclude that chronic binge alcohol exposure during pregnancy alters mTORC1 signaling pathway in the fetal hippocampus. We conjecture that this dysregulation of mTOR protein expression, its activity, and downstream proteins may play a critical role in FASD neurobiological phenotypes.

Rapamycin Improves Spatial Learning Deficits, Vulnerability to Alcohol Addiction and Altered Expression of the GluN2B Subunit of the NMDA Receptor in Adult Rats Exposed to Ethanol during the Neonatal Period

“…Although we did not evaluate the influence of ethanol on the mTOR signaling pathway, pretreatment with rapamycin before ethanol administration in neonatal rats mitigated the negative effects of neonatal ethanol exposure on rat behavior and neurochemical evaluation. These data support the previous finding that gestational binge alcohol exposure dysregulates the fetal hippocampal mTOR system, has an impact on mTORC1 signaling, which plays essential roles in brain development and alters the proteins that complex with hippocampal mTOR, the functions of which have also been implicated in brain developmental processes [33,82]. Furthermore, it has been previously indicated that inhibition of GluN2B in the orbitofrontal cortex attenuates alcoholdependent mTORC1 activation, alcohol seeking and habitual responding for alcohol.…”

Dose-related shifts in proteome and function of extracellular vesicles secreted by fetal neural stem cells following chronic alcohol exposure

“…However, there were also significant differences. For example, the dominant pathway overrepresentation with heavy exposure, was the mechanistic target of rapamycin (mTor) cellular response amino acid starvation, an established stress response in animal models of prenatal ethanol exposure [ 90 , 91 ], that is associated with inflammation and fetal brain injury [ 92 ] and disorganized cortical lamination [ 93 ].…”

Binge-like Prenatal Ethanol Exposure Causes Impaired Cellular Differentiation in the Embryonic Forebrain and Synaptic and Behavioral Defects in Adult Mice

“…Human and preclinical animal studies have reported significant neurobehavioral abnormalities in offspring after prolonged low-to high-dose prenatal ethanol exposure, i.e., exposure resulting in low-to-high BECs [ 78 , 79 , 80 , 81 , 82 , 83 ]. However, limited animal studies have investigated the effects of lower, moderate, and high ethanol doses administered acutely during specific developmental stages [ 47 , 84 , 85 , 86 ] and established the time, pattern, and dose of ethanol exposure to model heavy human drinking (i.e., 3–5 drinks in one sitting on 2 successive days).…”