Effects Of Prenatal Ethanol Exposure Research Articles

Folate administration ameliorates neurobehavioral effects of prenatal ethanol exposure

ABSTRACT Background: Prenatal ethanol exposure (PEE) induces heightened ethanol intake at adolescence in preclinical studies. Ethanol intake alters the absorption of folate, a methyl-group donor critical for numerous cellular functions. The prenatal administration of folate is, therefore, a promising approach to reduce the effects of PEE. Objectives: Experiment 1 determined if prenatal folate modulated the effects of PEE on ethanol intake, anxiety-like response, and exploratory behaviors (Experiment 1) in Wistar rats. Experiment 2 assessed, in rats not given PEE, if postnatal folate reversed effects of ethanol exposure at postnatal days 28–42. Experiment 3 assessed if folate altered blood ethanol levels (BELs). Methods: Experiment 1 involved 242 (125 male) adolescent Wistar rats derived from dams given folate (20 mg/kg, gestational days – GD- 13-20) + ethanol (2.0 g/kg, GD 17–20), ethanol, or vehicle only at pregnancy. Experiment 2 involved 29 male adolescents administered vehicle or ethanol doses co-administered or not with folate. In Experiment 3 twelve adult females were tested for BELs after folate administration. These tests were applied: intake tests, light dark box (LDB), elevated plus maze, open field and concentric square field. Results: PEE heightened ethanol intake (η2 ps = 0.06–07) and induced hyperactivity and a reduced latency to exit the white area of the LDB (η2 ps = 0.12–17). These effects were partially inhibited by folate (p > .05). Rats exposed to ethanol exposure at adolescence exhibited reduced motor activity (η2 p = .17), regardless of folate treatment. Folate did not affect BELs. Conclusion: Folate administration should be considered as a preventive or acute treatment to attenuate the neurobehavioral effects of PEE.

Effects of prenatal ethanol exposure on choline-induced long-term depression in the hippocampus.

Choline is an essential nutrient under evaluation as a cognitive enhancing treatment for fetal alcohol spectrum disorders (FASD) in clinical trials. As a result, there is increased pressure to identify therapeutic mechanism(s) of action. Choline is not only a precursor for several essential cell membrane components and signaling molecules but also has the potential to directly affect synaptic mechanisms that are believed important for cognitive processes. In the current work, we study how the direct application of choline can affect synaptic transmission in the dentate gyrus (DG) of hippocampal slices obtained from adolescent (postnatal days 21-28) Sprague-Dawley rats (Rattus norvegicus). The acute administration of choline chloride (2 mM) reliably induced a long-term depression (LTD) of field excitatory postsynaptic potentials (fEPSPs) in the DG in vitro. The depression required the involvement of M1 receptors, and the magnitude of the effect was similar in slices obtained from male and female animals. To further study the impact of choline in an animal model of FASD, we examined offspring from dams fed an ethanol-containing diet (35.5% ethanol-derived calories) throughout gestation. In slices from the adolescent animals that experienced prenatal ethanol exposure (PNEE), we found that the choline induced an LTD that uniquely involved the activation of N-methyl-d-aspartate (NMDA) and M1 receptors. This study provides a novel insight into how choline can modulate hippocampal transmission at the level of the synapse and that it can have unique effects following PNEE.NEW & NOTEWORTHY Choline supplementation is a nutraceutical therapy with significant potential for a variety of developmental disorders; however, the mechanisms involved in its therapeutic effects remain poorly understood. Our research shows that choline directly impacts synaptic communication in the brain, inducing a long-term depression of synaptic efficacy in brain slices. The depression is equivalent in male and female animals, involves M1 receptors in control animals, but uniquely involves NMDA receptors in a model of FASD.

Prenatal ethanol exposure impairs the formation of radial glial fibers and promotes the transformation of GFAPδ‑positive radial glial cells into astrocytes.

During embryonic cortical development, radial glial cells (RGCs) are the major source of neurons, and these also serve as a supportive scaffold to guide neuronal migration. Similar to Vimentin, glial fibrillary acidic protein (GFAP) is one of the major intermediate filament proteins present in glial cells. Previous studies confirmed that prenatal ethanol exposure (PEE) significantly affected the levels of GFAP and increased the disassembly of radial glial fibers. GFAPδ is a variant of GFAP that is specifically expressed in RGCs; however, to the best of our knowledge, there are no reports regarding how PEE influences its expression during cortical development. In the present study, the effects of PEE on the expression and distribution of GFAPδ during early cortical development were assessed. It was found that PEE significantly decreased the expression levels of GFAP and GFAPδ. Using double immunostaining, GFAPδ was identified to be specifically expressed in apical and basal RGCs, and was co-localized with other intermediate filament proteins, such as GFAP, Nestin and Vimentin. Additionally, PEE significantly affected the morphology of radial glial fibers and altered the behavior of RGCs. The loss of GFAPδ accelerated the transformation of RGCs into astrocytes. Using co-immunostaining with Ki67 or phospho-histone H3, GFAPδ+ cells were observed to be proliferative or mitotic cells, and ethanol treatment significantly decreased the proliferative or mitotic activities of GFAPδ+ RGCs. Taken together, the results suggested that PEE altered the expression patterns of GFAPδ and impaired the development of radial glial fibers and RGC behavior. The results of the present study provided evidence that GFAPδ may be a promising target to rescue the damage induced by PEE.

Choline Plus Working Memory Training Improves Prenatal Alcohol-Induced Deficits in Cognitive Flexibility and Functional Connectivity in Adulthood in Rats.

Fetal alcohol spectrum disorder (FASD) is the leading known cause of intellectual disability, and may manifest as deficits in cognitive function, including working memory. Working memory capacity and accuracy increases during adolescence when neurons in the prefrontal cortex undergo refinement. Rats exposed to low doses of ethanol prenatally show deficits in working memory during adolescence, and in cognitive flexibility in young adulthood. The cholinergic system plays a crucial role in learning and memory processes. Here we report that the combination of choline and training on a working memory task during adolescence significantly improved cognitive flexibility (performance on an attentional set shifting task) in young adulthood: 92% of all females and 81% of control males formed an attentional set, but only 36% of ethanol-exposed males did. Resting state functional magnetic resonance imaging showed that functional connectivity among brain regions was different between the sexes, and was altered by prenatal ethanol exposure and by choline + training. Connectivity, particularly between prefrontal cortex and striatum, was also different in males that formed a set compared with those that did not. Together, these findings indicate that prenatal exposure to low doses of ethanol has persistent effects on brain functional connectivity and behavior, that these effects are sex-dependent, and that an adolescent intervention could mitigate some of the effects of prenatal ethanol exposure.

VP27.04: Corpus callosum as an imaging biomarker of neurodevelopmental effects of prenatal ethanol exposure

VP27.04: Corpus callosum as an imaging biomarker of neurodevelopmental effects of prenatal ethanol exposure

Effects of prenatal ethanol exposure on acoustic characteristics of play fighting-induced ultrasonic vocalizations in juvenile rats

Juvenile rats display rough-and-tumble playing with conspecifics (play fighting behavior) and produce 22 and 50 kHz ultrasonic vocalizations (USVs). The 22 kHz USV is considered to reflect negative emotionality such as anxiety, fear, and distress, whereas the 50 kHz USV is considered to reflect positive emotionality such as joy, happiness, and satisfaction. USV is a sensitive tool for measuring emotionality in socially interactive situations. However, effects of prenatal ethanol-exposure on the acoustic characteristics of play fighting-induced USVs have remained unclear. In Experiment I, we recorded USVs produced by prenatally ethanol-exposed rats during play fighting on postnatal days (PNDs) 40–42 and examined the acoustic characteristics of negative and positive emotion-induced USVs. In Experiment II, we examined the anxiety levels through elevated plus maze testing on PNDs 37–39 and frequencies of playful attacks on PNDs 43–45 in ethanol-exposed rats. Ethanol was administered to pregnant rats in three gradually increased concentrations between gestational days (GDs) 8 and 20. From GDs 14 to 20, ethanol-containing tap water at concentrations of 30% and 15% (v/v) was administered to the high- and low-ethanol groups, respectively. Tap water without added ethanol was given to the control group. On PNDs 40–42, three rats from the same sex and same ethanol concentration group but from different litters were placed together into a playing cage for play fighting. The high-ethanol male triads displayed elevations of 20–35 kHz USVs reflecting negative emotionality and reductions of 45–70 kHz USVs reflecting positive emotionality compared with both the low-ethanol and control male triads. The high-ethanol male triads had prominent elevations of 20–35 kHz USVs with durations longer than 200 ms, whereas the control male triads did not produce such 20–35 kHz USVs at all. There was no difference in USV acoustic characteristics among the female triads. In addition, the high-ethanol male rats exhibited greater anxiety levels and less frequencies of play fighting than the control male rats. Altogether, we conclude that prenatal exposure to ethanol enhances negative emotionality such as anxiety and, accordingly, 20–35 kHz USVs reflecting negative emotionality are produced with a marked decrease in play fighting, suggesting difficulties in social interactions with conspecifics.

In-vivo hemodynamic imaging of acute prenatal ethanol exposure in fetal brain by photoacoustic tomography.

Prenatal ethanol exposure (PEE) can lead to structural and functional abnormalities in fetal brain. Although neural developmental deficits due to PEE have been recognized, the immediate effects of PEE on fetal brain vasculature and hemodynamics remain poorly understood. One of the major obstacles that preclude the rapid advancement of studies on fetal vascular dynamics is the limitation of the imaging techniques. Thus, a technique for noninvasive in-vivo imaging of fetal vasculature and hemodynamics is desirable. In this study, we explored the dynamic changes of the vessel dimeter, density and oxygen saturation in fetal brain after acute maternal ethanol exposure in the second-trimester equivalent murine model using a real-time photoacoustic tomography system we developed for imaging embryo of small animals. The results indicate a significant decrease in fetal brain vessel diameter, perfusion and oxygen saturation. This work demonstrated that PAT can provide high-resolution noninvasive imaging ability to monitor fetal vascular dynamics.

Egr1/p300/ACE signal mediates postnatal osteopenia in female rat offspring induced by prenatal ethanol exposure

Prenatal ethanol exposure induces developmental toxicities of multiple organs in offspring. Here, we investigate the effects of prenatal ethanol exposure on bone mass in postnatal offspring and explore its intrauterine programming mechanism. We found that prenatal ethanol exposure could induce bone dysplasia in fetuses and postnatal osteopenia in female offspring, accompanied by the sustained activation of the local renin-angiotensin systems (RAS) and inhibition of bone formation. Additionally, we also found that histone 3 lysine 9 acetylation (H3K9ac) and H3K27ac levels in the promoter region of angiotensin-converting enzyme (ACE) were increased in female offspring exposed to ethanol during pregnancy. In vitro, ethanol suppressed the formation of mineralized nodules and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), which was blocked by enalapril. Furthermore, ethanol promoted the expression and nuclear translocation of early growth response factor 1 (Egr1), which participated in the promotion of histone acetylation of ACE and subsequent RAS activation, by recruiting p300 and binding to the ACE promoter region directly. These findings indicate that the sustained activation of the local RAS might participate in bone dysplasia in fetus and postnatal osteopenia in the female offspring, while the Egr1/p300/ACE signal might be a key promoter of the sustained activation of the local RAS of the long bone.

Early exposure to environmental enrichment modulates the effects of prenatal ethanol exposure upon opioid gene expression and adolescent ethanol intake

Prenatal ethanol exposure (PEE) promotes ethanol consumption in the adolescent offspring accompanied by the transcriptional regulation of kappa opioid receptor (KOR) system genes. This study analysed if environmental enrichment (EE, from gestational day 20 to postnatal day 26) exerts protective effects upon PEE-modulation of gene expression, ethanol intake and anxiety responses. Pregnant rats were exposed to PEE (0.0 or 2.0 g/kg ethanol, gestational days 17–20) and subsequently the dam and offspring were reared under EE or standard conditions. PEE upregulated KOR mRNA levels in amygdala (AMY) and prodynorphin (PDYN) mRNA levels in ventral tegmental area (VTA) with the latter effect associated with lower DNA methylation at the gene promoter. These effects were normalized by exposure to EE. PEE modulated BDNF mRNA levels in VTA and Nucleus accumbens (AcbN), and EE mitigated the changes in AcbN. EE induced a protective effect on ethanol intake and preference, an effect more noticeable in males than in females, and in prenatal vehicle-treated (PV) than in PEE rats. The male offspring drank significantly less ethanol than the female offspring. The latter result suggests that the protective effect of EE on ethanol drinking may only emerge at lower levels of drinking. In the dams, PEE induced an upregulation of PDYN and KOR in AcbN. PDYN gene expression was normalized by exposure to EE. These results suggest that EE is a promising treatment to inhibit the effects of PEE. The results confirm that PEE effects are mediated by alterations in the transcriptional regulation of KOR system genes.

Impaired Bidirectional Synaptic Plasticity in Juvenile Offspring Following Prenatal Ethanol Exposure.

The hippocampus is particularly vulnerable to the teratogenic effects of prenatal ethanol exposure (PNEE), and hippocampal structural and functional deficits are thought to contribute to the learning and memory deficits that are a hallmark feature of fetal alcohol spectrum disorders. Sprague Dawley dams were exposed to a liquid diet that contained EtOH (35.5% EtOH-derived calories) throughout gestation, and then, PNEE juvenile (P21-28) male and female offspring were used for in vitro electrophysiological recordings. We examined long-term potentiation (LTP), long-term depression (LTD), and depotentiation in the medial perforant path input to the dentate gyrus (DG) to determine the impact of PNEE on the dynamic range of bidirectional synaptic plasticity in both sexes. PNEE reduced the responsiveness of the DGs of male but not in female offspring, and this effect was no longer apparent when GABAergic signaling was inhibited. There was also a sex-specific LTD impairment in males, but increasing the duration of the conditioning stimulus could overcome this deficit. The magnitude of LTP was also reduced, but in both sexes following PNEE. This appears to be an increase in the threshold for induction, not in capacity, as the level of LTP induced in PNEE animals was increased to control levels when additional conditioning stimuli were administered. These data are the first to describe, in a single study, the impact of PNEE on the dynamic range of bidirectional synaptic plasticity in the juvenile DG in both males and in females. The data suggest that PNEE increases the threshold for LTP in the DG in both sexes, but produces a sex-specific increase in the threshold for LTD in males These alterations reduce the dynamic range for synaptic plasticity in both sexes.

Prenatal ethanol intoxication and maternal intubation stress alter cell survival and apoptosis in the postnatal development of rat hippocampus

It is well known that the fetal ethanol exposure and prenatal stress may have adverse effects on brain development. Interestingly, some morphological and functional recovery from their teratogenic effects that take place during brain maturation. However, mechanisms that underlie this recovery are not fully elucidated. The aim of this study was to examine whether the postnatal attenuation of fetal alcohol - and maternal stress‑induced morphological and functional deficits correlates with compensatory changes in the expression/activation of the brain proteins involved in inflammation, cell survival and apoptosis. In this project, we investigated the hippocampus which belongs to the brain regions most susceptible to the adverse effects of prenatal ethanol exposure. Pregnant rat dams were administered ethanol (A) or isocaloric glucose solution (IC) by a gastric intubation during gestational days 7-20. The pure control group received ad libitum laboratory chow and water with no other treatment. The hippocampi of fetal-ethanol and control pups were examined at the postnatal day (PD)1, PD10, PD30 and PD60. Moderate fetal-ethanol exposure and prenatal intubation stress caused a significant increase in molecular factors relating to inflammation (iNOS) and cell survival/apoptosis pathways (PTEN, GSK-3 and ERK) at birth, with a rapid compensation from these developmental deficits upon removal of alcohol at PD10. Indeed, an increase in ERK1/2 and JNK1/2 activation at PD30 was observed with ethanol consumption. It indicates that the recovery process in A and IC brains started soon after the birth upon the ethanol and stressor withdrawal and continued until the adulthood.

Prenatal ethanol exposure attenuates sensitivity to the aversive effects of ethanol in adolescence and increases adult preference for a 5% ethanol solution in males, but not females.

The present set of experiments investigated the effects of a moderate dose of ethanol (2g/kg; 20% v/v intragastrically) during late gestation (G17-20 [gestational day]) on ethanol-induced conditioned taste aversion (CTA) in adolescence, and on ethanol consumption during adolescence and early adulthood. In experiment 1, male and female Sprague-Dawley rats were given 30-min access to a sweetened "supersaccharin" (SS) solution or sodium chloride (NaCl), followed by an intraperitoneal injection of 20% ethanol (0, 1, 1.25, or 1.5g/kg) for three conditioning/test sessions. Among animals conditioned with SS, prenatally ethanol-exposed males exhibited attenuated ethanol-induced CTA relative to males prenatally gavaged with water or non-manipulated, whereas prenatal treatment had no effect on CTA in females. Among animals conditioned with NaCl, there were no exposure group differences in males, with modest evidence for attenuated CTA in prenatally ethanol-exposed females. In experiment 2, the effects of prenatal ethanol exposure on ethanol consumption in adolescents (P35±1 day [postnatal day]) and adults (P56-60) were explored. At the beginning of the dark cycle, pair-housed rats were given three bottles containing 0, 5, and 10% ethanol for 18h every other day (i.e., Monday, Wednesday, Friday) for 3 weeks. Relative to water controls, adult males prenatally exposed to ethanol showed greater preference and more intake (g/kg) of 5% ethanol, while showing lower intake of 10% ethanol. These intake and preference differences were not evident in adolescent males. Among females at both ages, ethanol-exposed animals showed lower preference and intake (g/kg) of 5% ethanol than their water-exposed controls. Thus, moderate ethanol exposure during late gestation produced a largely male-specific attenuation in the aversive effects of ethanol during adolescence that could contribute to later increases in preference and intake of a 5% ethanol solution, although this emergent effect was not evident in adolescence (or in females), but only manifested in adulthood.

Long-Lasting Effects of Prenatal Ethanol Exposure on Fear Learning and Development of the Amygdala

Prenatal ethanol exposure (PrEE) produces developmental abnormalities in brain and behavior that often persist into adulthood. We have previously reported abnormal cortical gene expression, disorganized neural circuitry along with deficits in sensorimotor function and anxiety in our CD-1 murine model of fetal alcohol spectrum disorders, or FASD (El Shawa et al., 2013; Abbott et al., 2016). We have proposed that these phenotypes may underlie learning, memory, and behavioral deficits in humans with FASD. Here, we evaluate the impact of PrEE on fear memory learning, recall and amygdala development at two adult timepoints. PrEE alters learning and memory of aversive stimuli; specifically, PrEE mice, fear conditioned at postnatal day (P) 50, showed deficits in fear acquisition and memory retrieval when tested at P52 and later at P70–P72. Interestingly, this deficit in fear acquisition observed during young adulthood was not present when PrEE mice were conditioned later, at P80. These mice displayed similar levels of fear expression as controls when tested on fear memory recall. To test whether PrEE alters development of brain circuitry associated with fear conditioning and fear memory recall, we histologically examined subdivisions of the amygdala in PrEE and control mice and found long-term effects of PrEE on fear memory circuitry. Thus, results from this study will provide insight on the neurobiological and behavioral effects of PrEE and provide new information on developmental trajectories of brain dysfunction in people prenatally exposed to ethanol.

Effects of prenatal ethanol exposure on acoustic characteristics of ultrasonic vocalizations in rat pups

Rat pups produce ultrasonic vocalizations (USVs) on isolation from their dam. Ultrasonic vocalization is a sensitive tool for evaluating social behavior between pups and their dam. Prenatal ethanol-exposure leads to a reduction in USVs and have the potential of inducing difficulties in social behavior between pups and their dam. However, effects of prenatal ethanol-exposure on the acoustic characteristics of USVs remain unclear. In this study, we recorded USVs produced by rat pups that were prenatally exposed to ethanol and examined their acoustic characteristics. Ethanol was administered to 13 pregnant rats in three stages by gradually increasing concentrations between gestational days (GDs) 8–20. From GDs 14–20, ethanol-containing tap water at concentrations of 30% and 15% (v/v) was administered to the high- and low-ethanol groups, respectively. Tap water without ethanol was given to the control group. On postnatal days (PNDs) 4, 8, 12, and 16, individual newly-born pups were isolated from their dam and littermates and USVs produced by them were recorded for 5 min. The number of USVs in the high-ethanol group was greater than that in both low-ethanol and control groups on PND 12. The mean, minimum, and maximum fundamental frequencies of USVs were elevated in the high-ethanol group compared with that in both low-ethanol and control groups. Higher amplitudes of USVs were produced by male pups in the high-ethanol group than in those in both low-ethanol and control groups on PND 12. These results suggest that prenatal ethanol exposure changed emotionality and accordingly, the high-ethanol group produced more USVs as distress calls.

Ethanol Exposure In Utero Disrupts Radial Migration and Pyramidal Cell Development in the Somatosensory Cortex.

Deficits in sensory processing in Fetal Alcohol Spectrum Disorders (FASD) implicate dysfunction in the somatosensory cortex. However, the effects of prenatal ethanol exposure on the development of this region await elucidation. Here, we used an established mouse model of FASD with binge-type ethanol exposure from embryonic day 13.5-16.5 to investigate the effects of prenatal ethanol exposure on pyramidal neurons in the somatosensory cortex. Specifically, we focused on the radial migration of primordial pyramidal neurons during embryonic corticogenesis and their morphology and function during active synaptogenesis in early postnatal development. We found that prenatal ethanol exposure resulted in aberrant radial migration, particularly affecting the populations of postmitotic pyramidal neurons. In addition, there was an enduring effect of prenatal ethanol exposure on glutamate-mediated synaptic transmission in layer V/VI pyramidal neurons. This persisted beyond a transient decrease in pyramidal neuron dendritic complexity that was evident only during early postnatal development. Adolescent mice exposed prenatally to ethanol also displayed decreased tactile sensitivity, as revealed by a modified adhesive tape removal assay. Our findings demonstrate the persistent effects of binge-type in utero ethanol exposure on pyramidal neuron form and function and ultimately sensory processing, the latter being reminiscent of that seen in individuals with FASD.

Ethanol-Induced Neurodegeneration and Glial Activation in the Developing Brain.

Ethanol induces neurodegeneration in the developing brain, which may partially explain the long-lasting adverse effects of prenatal ethanol exposure in fetal alcohol spectrum disorders (FASD). While animal models of FASD show that ethanol-induced neurodegeneration is associated with glial activation, the relationship between glial activation and neurodegeneration has not been clarified. This review focuses on the roles of activated microglia and astrocytes in neurodegeneration triggered by ethanol in rodents during the early postnatal period (equivalent to the third trimester of human pregnancy). Previous literature indicates that acute binge-like ethanol exposure in postnatal day 7 (P7) mice induces apoptotic neurodegeneration, transient activation of microglia resulting in phagocytosis of degenerating neurons, and a prolonged increase in glial fibrillary acidic protein-positive astrocytes. In our present study, systemic administration of a moderate dose of lipopolysaccharides, which causes glial activation, attenuates ethanol-induced neurodegeneration. These studies suggest that activation of microglia and astrocytes by acute ethanol in the neonatal brain may provide neuroprotection. However, repeated or chronic ethanol can induce significant proinflammatory glial reaction and neurotoxicity. Further studies are necessary to elucidate whether acute or sustained glial activation caused by ethanol exposure in the developing brain can affect long-lasting cellular and behavioral abnormalities observed in the adult brain.

Animal Models for Medication Development and Application to Treat Fetal Alcohol Effects.

Ethanol consumption during pregnancy can have lifelong consequences for the offspring, their family and society. Fetal alcohol spectrum disorders (FASD) include a range of physical and behavioral effects with the most significant impact occurring as a result of the effects of ethanol on the developing central nervous system (CNS). To date, there are no FDA approved drugs that have been tested that prevent/reduce or specifically treat the symptoms of FASD. There are several promising lines of research from rodent models aimed at reducing the neurotoxic effects of ethanol on the developing CNS or in treating the resulting behavioral impairments but these have not yet moved to clinical testing. The current review discusses some of the most promising targets for intervention and provides a review of the past and ongoing efforts to develop and screen pharmacological treatments for reducing the effects of prenatal ethanol exposure.

Gypenosides protected the neural stem cells in the subventricular zone of neonatal rats that were prenatally exposed to ethanol.

Fetal alcohol spectrum disorder (FASD) can cause severe mental retardation in children who are prenatally exposed to ethanol. The effects of prenatal and early postnatal ethanol exposure on adult hippocampal neurogenesis have been investigated; however, the effects of prenatal ethanol exposure on the subventricular zone (SVZ) have not. Gypenosides (GPs) have been reported to have neuroprotective effects in addition to other bioactivities. The effects of GPs on neural stem cells (NSCs) in the FASD model are unknown. Here, we test the effect of prenatal ethanol exposure on the neonatal SVZ, and the protection potential of GPs on NSCs in FASD rats. Our results show that prenatal ethanol exposure can suppress the cell proliferation and differentiation of neural stem cells in the neonatal SVZ and that GPs (400 mg/kg/day) can significantly increase the cell proliferation and differentiation of neural stem cells inhibited by ethanol. Our data indicate that GPs have neuroprotective effects on the NSCs and can enhance the neurogenesis inhibited by ethanol within the SVZ of neonatal rats. These findings provide new evidence for a potential therapy involving GPs for the treatment of FASD.

Advances in the development of novel antioxidant therapies as an approach for fetal alcohol syndrome prevention.

Ethanol is the most common human teratogen, and its consumption during pregnancy can produce a wide range of abnormalities in infants known as fetal alcohol spectrum disorder (FASD). The major characteristics of FASD can be divided into: (i) growth retardation, (ii) craniofacial abnormalities, and (iii) central nervous system (CNS) dysfunction. FASD is the most common cause of nongenetic mental retardation in Western countries. Although the underlying molecular mechanisms of ethanol neurotoxicity are not completely determined, the induction of oxidative stress is believed to be one central process linked to the development of the disease. Currently, there is no known effective strategy for prevention (other than alcohol avoidance) or treatment. In the present review we will provide the state of art in the evidence for the use of antioxidants as a potential therapeutic strategy for the treatment using whole-embryo and culture cells models of FASD. We conclude that the imbalance of the intracellular redox state contributes to the pathogenesis observed in FASD models, and we suggest that antioxidant therapy can be considered a new efficient strategy to mitigate the effects of prenatal ethanol exposure.

Impact of combined prenatal ethanol and prenatal stress exposures on markers of activity-dependent synaptic plasticity in rat dentate gyrus

Prenatal ethanol exposure and prenatal stress can each cause long-lasting deficits in hippocampal synaptic plasticity and disrupt learning and memory processes. However, the mechanisms underlying these perturbations following a learning event are still poorly understood. We examined the effects of prenatal ethanol exposure and prenatal stress exposure, either alone or in combination, on the cytosolic expression of activity-regulated cytoskeletal (ARC) protein and the synaptosomal expression of AMPA-glutamate receptor subunits (GluA1 and GluA2) in dentate gyrus of female adult offspring under baseline conditions and after 2-trial trace conditioning (TTTC). Surprisingly, baseline cytoplasmic ARC expression was significantly elevated in both prenatal treatment groups. In contrast, synaptosomal GluA1 receptor subunit expression was decreased in both prenatal treatment groups. GluA2 subunit expression was elevated in the prenatal stress group. TTTC did not alter ARC levels compared to an unpaired behavioral control (UPC) group in any of the 4 prenatal treatment groups. In contrast, TTTC significantly elevated both synaptosomal GluA1 and GluA2 subunit expression relative to the UPC group in control offspring, an effect that was not observed in any of the other 3 prenatal treatment groups. Given ARC's role in regulating synaptosomal AMPA receptors, these results suggest that prenatal ethanol-induced or prenatal stress exposure-induced increases in baseline ARC levels could contribute to reductions in both baseline and activity-dependent changes in AMPA receptors in a manner that diminishes the role of AMPA receptors in dentate gyrus synaptic plasticity and hippocampal-sensitive learning.