Model Of Fetal Alcohol Syndrome Research Articles

Ercc6l, a gene of SNF2 family, may play a role in the teratogenic action of alcohol

The expression profile of a newly identified mouse nucleotide excision repair (NER) gene, Ercc6l, was investigated in a mouse model of fetal alcohol syndrome (FAS). In test 1, whole-mount in situ hybridization showed Ercc6l expressed mainly in the neural tube and heart of 10.5-day embryo. However, the expressions in both of the two organs were significantly down regulated after in uterus alcohol exposure from embryonic day (ED) 6–10, which was in accordance with the result of semi-quantitative RT-PCR. In test 2, the dams were given alcohol intragastrically from ED 6–15, and Northern blot of Ercc6l mRNA was carried out with five major embryo organs on ED 15.5, which were heart, brain, kidney, liver and lung. Ercc6l expression in 15.5-day embryonic brain and heart, which are the most commonly affected organs of FAS, were both decreased by alcohol exposure. The expressions in the other three organs were unaffected. From the results, we considered that Ercc6l might play a role in the teratogenic action of alcohol.

Early alcohol exposure impairs ocular dominance plasticity throughout the critical period

Animal models of fetal alcohol syndrome (FAS) have revealed an impairment of sensory neocortex plasticity. Here, we examine whether early alcohol exposure leads to a permanent impairment of ocular dominance plasticity (OD) or to an alteration in the timing of the critical period. Ferrets were exposed to alcohol during a brief period of development prior to eye opening and effects of monocular deprivation examined during early, mid and late critical period. Single-unit electrophysiology revealed markedly reduced OD plasticity at every age examined. This finding provides evidence that early alcohol exposure does not affect the timing or duration of the critical period of OD plasticity and suggests an enduring impairment of neural plasticity in FAS.

Impaired development of mitochondria plays a role in the central nervous system defects of fetal alcohol syndrome

Alcohol consumption during pregnancy can induce a wide spectrum of adverse effects in offspring. Microcephaly and mental retardation are two major defects of central nervous system (CNS). Most mechanism studies of alcohol-related CNS defects have been focused on the morphologically abnormal tissues, and more attention has been paid to nuclear alteration as opposed to organelle development. A mouse model of fetal alcohol syndrome (FAS) was used to investigate the effect of alcohol on fetal cerebral mitochondria development. Pregnant mice were given different doses of ethanol intragastrically from GD6 to GD15. Fetal cerebral mitochondria were isolated and analyzed on GD18. Excessive cell apoptosis was found in the cerebra of prenatal alcohol exposure fetuses. Proliferation and differentiation of fetal cerebral mitochondria were inhibited by alcohol. Affected mitochondrial volume constriction and adenosine triphosphate (ATP) accumulation, reduced activities of respiratory chain complex I and IV and ATP synthase were detected in the cerebral tissue without obvious malformed appearance. Impaired mitochondria development plays a role in the CNS defects induced by prenatal alcohol exposure.

Alcohol brain NMDA subunit expression altered by in utero alcohol exposure

Alcohol-related neurodevelopmental disorders are contributors to long-term learning disabilities. Using a model for fetal alcohol syndrome (FAS), we have shown that prenatal alcohol exposure results in adult learning deficits of unknown mechanism. In the developing hippocampus, the NMDA receptor subunit NR2B triggers long-term potentiation, fundamental to learning and memory; these are supplemented by less plastic NR2A subunits in the adult. To understand the mechanism of alcohol-induced learning deficits in FAS, we evaluated NR2B and NR2A expression in the embryo and adult.

Prevention of alcohol-induced delays in developmental milestones and learning abnormalities in a model of fetal alcohol syndrome

Prevention of alcohol-induced delays in developmental milestones and learning abnormalities in a model of fetal alcohol syndrome

Ethanol exposure alters zebrafish development: A novel model of fetal alcohol syndrome

Prenatal exposure to alcohol has been shown to produce the overt physical and behavioral symptoms known as fetal alcohol syndrome (FAS) in humans. Also, it is believed that low concentrations and/or short durations of alcohol exposure can produce more subtle effects. The purpose of this study was to investigate the effects of embryonic ethanol exposure on the zebrafish ( Danio rerio) in order to determine whether this species is a viable animal model for studying FAS. Fertilized embryos were reared in varying concentrations of ethanol (1.5% and 2.9%) and exposure times (e.g., 0–8, 6–24, 12–24, and 48–72 h postfertilization; hpf); anatomical measures including eye diameter and heart rate were compared across groups. Results found that at the highest concentration of ethanol (2.9%), there were more abnormal physical distortions and significantly higher mortality rates than any other group. Embryos exposed to ethanol for a shorter duration period (0–8 hpf) at a concentration of 1.5% exhibited more subtle effects such as significantly smaller eye diameter and lower heart rate than controls. These results indicate that embryonic alcohol exposure affects external and internal physical development and that the severity of these effects is a function of both the amount of ethanol and the timing of ethanol exposure. Thus, the zebrafish represents a useful model for examining basic questions about the effects of embryonic exposure to ethanol on development.

Protective peptides that are orally active and mechanistically nonchiral.

Previous reports identified two peptides that mimic the action of neuroprotective proteins derived from astrocytes. These peptides, NAPVSIPQ and SALLRSIPA, prevent neuronal cell death produced by electrical blockade, N-methyl-d-aspartate, and beta-amyloid peptide (25-35). In the present study, all d-amino acid peptides of NAPVSIPQ and SALLRSIPA were synthesized and compared respectively to the corresponding all l-amino acid peptides. In rat cerebral cortical test cultures cotreated with 1 microM tetrodotoxin, the d-amino acid peptides produced similar potency and efficacy for neuroprotection as that observed for their respective l-amino acid peptides. Since all these peptides tested individually exhibited attenuation of efficacy at concentrations of >10 pM, combinations of these peptides were tested for possible synergies. Equimolar d-NAPVSIPQ and d-SALLRSIPA combination treatment produced potent neuroprotection (EC(50), 0.03 fM) that did not attenuate with increasing concentrations. Similarly, the combination of l-NAPVSIPQ and d-SALLRSIPA also had high potency (EC(50), 0.07 fM) without attenuation of efficacy. Combined administration of peptides was tested in a model of fetal alcohol syndrome and in a model of learning impairment: apolipoprotein E knockout mice. Intraperitoneal administration of d-NAPVSIPQ plus d-SALLRSIPA to pregnant mice (embryonic day 8) attenuated fetal demise after treatment with an acute high dose of alcohol. Furthermore, oral administration of d-NAPVSIPQ plus d-SALLRSIPA significantly increased fetal survival after maternal alcohol treatment. Apolipoprotein E knockout mice injected with d-NAPVSIPQ plus d-SALLRSIPA showed improved performance in the Morris water maze. These studies suggest therapeutic potential for the combined administration of neuroprotective peptides that can act through a mechanism independent of chiral recognition.

Time-lapse analysis of ethanol's effects on axon growth in vitro.

The cortical abnormalities found in animal models of fetal alcohol syndrome (FAS) suggest a disruption of axon growth. After emerging from the cell body, axons exhibit saltatory growth, cycling between periods of extension and periods of retraction. The timing of neuronal process outgrowth an the balance between extension and retraction together determine the net rate of axon elongation, and may be independently regulated. In this study, we used time-lapse digital microscopy and custom-designed analytic software to assess the effects of ethanol on the growth of axons from embryonic rat hippocampal pyramidal neurons in culture during 24 h of development, beginning approximately 7 h after plating. We recorded the amount of time elapsed before axons emerged, the relative amount of time spent in periods of growth and nongrowth, and the rate and direction of change in axon length during both periods of growth and nongrowth. The initiation of axonal outgrowth was significantly delayed by ethanol in a dose-dependent fashion at concentrations in the medium at or above 100 mg/dl. However, once established, axons exhibited accelerated growth in the presence of ethanol. This increase in overall growth rate was primarily due to a significant decrease in axon retraction during nongrowth periods. Ethanol did not affect the duration or frequency of growth and nongrowth periods. We propose, therefore, that mechanisms underlying ethanol-mediated changes in axon growth are linked to signaling events that differentially regulate outgrowth and retraction.

Differential expression of c- fos in a mouse model of fetal alcohol syndrome

Objective Fetal alcohol syndrome (FAS) results in stillbirth, fetal growth restriction, and mental retardation with injury attributed to oxidative stress. Our objective was to identify signal transduction pathways expressed in a model of FAS and to quantify expression of c- fos, a gene in the stress signal pathway. Study design Timed, pregnant C57Bl6/J mice were injected on E8 with saline solution or alcohol. RNA was extracted from decidua and embryo 6 and 24 hours later. Microarray analysis was used to screen gene pathways. Differential gene expression was confirmed using real-time polymerase chain reaction with results presented as the ratio of c- fos concentration to that of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Results Differential gene expression between alcohol and control was noted for stress signal pathway genes including c- fos. Real-time polymerase chain reaction demonstrated that c- fos messenger RNA expression was greater in the alcohol than control decidua at 6 hours after injection ( P<.01). This effect persisted at 24 hours ( P<.01). There was no difference in c- fos expression in embryos whose mothers received alcohol versus control after 6 hours ( P = .12) or 24 hours ( P = .89). Conclusion Alcohol administration during pregnancy results in differential gene expression in the stress signal pathway, particularly in c- fos. C- fos expression in the decidua increases from 6 to 24 hours after alcohol injection, but does not change in the embryo, which may contribute to alcohol-induced damage in FAS.

The role of activity-dependent neuroprotective protein in a mouse model of fetal alcohol syndrome

Objective Fetal alcohol syndrome (FAS) is the most common nongenetic cause of mental retardation. Peptides NAPVSIPQ (NAP) and SALLRSIPA (SAL), related to activity-dependent neuroprotective protein (ADNP), prevent alcohol-induced damage in a mouse model of FAS. Our objective was to characterize ADNP in this model to relate this protein to the mechanisms of damage and peptide neuroprotection. Study design Timed, pregnant C57Bl6/J mice were treated on day 8. Groups were control, alcohol, peptide pretreatment, or peptide alone. Embryo and decidua were harvested at 6 and 24 hours and 10 days. To evaluate ADNP expression, real-time polymerase chain reaction was performed with results presented as the ratio of ADNP-to-glyceraldehyde-3-phosphate dehydrogenase (GAPDH) concentration. Analysis of variance was performed for overall comparisons with P<.05 considered significant. Results At 6 hours, there was no difference in ADNP between alcohol-exposed embryos compared with control embryos. At 24 hours, there was an increase in ADNP in alcohol-exposed embryos compared with controls ( P<.001); these findings persisted at 10 days ( P<.001). In the decidua at 6 hours, there was no difference between alcohol and control. At 24 hours, there was greater ADNP in alcohol-exposed decidua compared with controls ( P<.001), which did not persist at 10 days ( P = .97). Peptide pretreatment did not prevent the alcohol-induced increase in ADNP in embryo or decidua. Conclusion Alcohol increased embryonic and decidual ADNP expression at 24 hours and it persisted in the embryo for 10 days. Because ADNP is a known neuroprotectant, these findings suggest that it may be released as a protective mechanism in FAS. Changes in the embryo were persistent suggesting that the embryo is more vulnerable to alcohol-induced damage than the mother.

Critical periods for ethanol-induced cell loss in the hippocampal formation

Rodent models of fetal alcohol syndrome (FAS) have revealed discrepant findings in ethanol's (EtOH) ability to alter the survival of principal neurons within hippocampal areas CA1, CA3 and the dentate gyrus (DG). One issue is the lack of systematic examination of the timing of EtOH exposure over key periods of hippocampal cell development. The present study examined whether systematic developmental EtOH exposure produces long-term hippocampal cell loss that is related to a specific time course in which either generation, migration or synaptogenic events in this neural region occurs. EtOH treatment occurred during the periods equivalent to the first, second, third and all three trimesters in humans using similar administration procedures for both mothers and pups. Unbiased stereological estimates of the total number of pyramidal and granule cells within hippocampal regions CA1, CA3 and DG were performed when rats reached adulthood. The findings confirm previous reports that area CA1 is highly susceptible to EtOH exposure that occurs during either the early neonatal period or all three trimesters equivalent, while areas CA3 and DG are more resistant to EtOH-induced insult during all periods of hippocampal development examined.

Ultrasonic vocalizations and maternal-infant interactions in a rat model of fetal alcohol syndrome.

When isolated from their dams and littermates, rat pups emit ultrasonic vocalizations to elicit attention and retrieval from their dams. This study examined the effects of perinatal alcohol exposure on ultrasonic vocalizations and maternal-infant interactions. Alcohol was administered throughout gestation to the dams and during the early postnatal period to the pups. Control groups consisted of a nontreated control and an intubated, pair-fed control. Ultrasonic vocalizations were measured on postnatal day (PD) 5 under varying conditions of isolation. Maternal behaviors were examined on PD2, 4, 6, 8, and 10. Maternal behaviors were not significantly affected by prior alcohol administration to either the dams or the pups. However, ethanol-exposed rat pups vocalized more on PD5 than controls regardless of condition. The heightened vocalization response of the ethanol-exposed pups might be an underlying factor in the persistent effects of perinatal ethanol exposure on social behavior.

Morphologic and neurotoxic effects of ethanol vary with timing of exposure in vitro

Results of investigations with animal models of fetal alcohol syndrome (FAS) seem to indicate that neuronal vulnerability to ethanol-induced cell death may be correlated with specific developmental events. In the present study, we sought to test this observation in a cell culture model of neuronal development in which morphogenesis as well as survival could be assessed. Using embryonic rat hippocampal pyramidal neurons in primary cultures, we compared the sensitivity of neurons to ethanol added, at 400 mg/dl, to the medium at different times relative to the development of axons and dendrites. Quantitative morphometric analysis was performed by using phase contrast at 12 h (0.5 day) and 24 h (1 day), or fluorescence microscopy after microtubule-associated protein-2 (MAP2) immunostaining at 6 and 14 days. Survival was assessed by counting the number of neurons per unit area of the substrate at 14 days. Addition of ethanol 1 day after plating, when most neurons had developed an axon, had no effect on survival up to 14 days in vitro, but resulted in significantly shorter, less branched dendrites than observed when ethanol was added 2 h after plating. Despite the shorter duration of ethanol exposure, the addition of ethanol on day 6, after rapid growth of dendrites and synapses had begun, resulted in loss of all but about one third of the neurons by 14 days. This supports the suggestion that increased neuronal vulnerability to the morphoregulatory effects of ethanol is correlated with the establishment of polarity, but that the sensitivity of neurons to the cytotoxic effects of ethanol occurs later, when dendrites and synapses are rapidly forming.

Vasoactive intestinal peptide mRNA and immunoreactivity are decreased in fetal alcohol syndrome model.

Vasoactive intestinal peptide (VIP) regulates growth in the early post-implantation embryo. Previous work has demonstrated that peptide agonists (SALLRSIPA and NAPVSIPQ) from downstream mediators that are regulated by VIP were able to prevent the alcohol-induced fetal death, growth restriction and microcephaly associated with fetal alcohol syndrome. Here we evaluated the role of VIP in this mouse model of fetal alcohol syndrome, to determine if fetal or maternal levels of VIP are altered. In addition, we evaluated whether peptide treatment would alter the effects of alcohol on VIP levels. Treatment groups included control, alcohol, and alcohol+peptides. VIP levels were measured with enzyme immunoassay [EIA] (Peninsula Laboratories, Belmont, CA). Quantitation of VIP expression was measured with rt-PCR using mimic cDNA primers. Embryo/decidual VIP levels were similar in control and alcohol-treated groups 6 h after treatment. However, in the embryo/deciduas at 12 and 24 h, VIP levels were below the EIA's detection limit in the alcohol-treated groups, and significantly lower than the control or peptide-pretreated groups (p<0.05). Maternal cortex VIP levels were undetectable and significantly lower in the alcohol-treated group than control or peptide+alcohol group at 6 and 12 h (p<0.001). VIP mRNA expression was quantitated in the embryo and deciduas, with a significant decline noted at 6 h to 58% of control levels (p=0.02). Pretreatment with the peptides attenuated the alcohol-induced decrease in VIP mRNA. These studies demonstrate that treatment with alcohol can decrease the expression and immunoreactivity of VIP in both maternal and fetal tissues. This alcohol-induced loss of a recognized regulator of embryonic growth and differentiation may contribute to the sequelae of toxicity observed in fetal alcohol syndrome.

In utero ethanol suppresses cerebellar activator protein-1 and nuclear factor-kappa B transcriptional activation in a rat fetal alcohol syndrome model.

A model of fetal alcohol syndrome was used to investigate prenatal ethanol effects on cerebellar transcription factors. Pregnant Sprague-Dawley rats were divided into three treatment groups: ethanol-exposed (E), calorically matched pair-fed (PF), and freely fed ad libitum (AL) groups. Ethanol exposure was stopped 2 days before parturition. The DNA binding in neonatal cerebella of the redox-sensitive transcription factors nuclear factor-kappa B (NF-kappa B) and activator protein-1 (AP-1) were determined by electrophoretic mobility shift assays. On the first postnatal day (PD1), there was decreased activation of these transcription factors in the E group relative to the control groups. The PD1 transcriptional effects were reversed as the neonate underwent development without further ethanol exposure. Western blot studies showed no corresponding decreases in protein amounts of both AP-1 and NF-kappa B components on PD1. Postnatal glutathione levels and catalase activity, as measures of oxidative stress hypothesized to be a probable cause of the transcriptional effects, showed no statistically significant effects attributable to ethanol. Examination of prenatal cerebella on embryonic day 20 (EM20), a time during ethanol exposure, showed DNA-binding trends similar to those of PD1. EM20 Western blot studies showed decreases in the levels of the active form of glycogen synthase kinase-3 (GSK-3). GSK-3 inhibition was reversed by PD1. Blocking of GSK-3 activity with gestational dietary lithium diminished both AP-1 and NF-kappa B DNA binding. Thus, prenatal ethanol exposure has the effect of diminishing pro-survival transcriptional activation, an effect possibly mediated by changes in GSK-3 activity.

Chronic Ethanol Treatment and Withdrawal Alter ACPD‐Evoked Calcium Signals in Developing Purkinje Neurons

Alcohol exposure during human fetal development can result in fetal alcohol syndrome, a condition characterized by central nervous system dysfunction. Detailed studies in animal models of fetal alcohol syndrome show that the cerebellar region is particularly sensitive to alcohol exposure during early development; however, the cellular mechanisms underlying the alcohol sensitivity of the immature cerebellum are poorly understood. Primary neuronal cultures of cerebellar cells were prepared from embryonic day 20 rat pups. Cultures were exposed to ethanol (33 mM; 150 mg/100 ml) during the main period of morphological development of the Purkinje neurons, from 6 to 17 days in vitro. After the ethanol treatment, the response of Purkinje neurons to the selective metabotropic glutamate receptor (mGluR) agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD; 300 microM) was examined in parallel fura-2 Ca2+ imaging and current-clamp experiments. In an additional set of experiments, ethanol-treated cultures were allowed to withdraw from ethanol overnight before recordings were performed. In Ca2+ imaging studies, the mean peak amplitude of ACPD-evoked Ca2+ signals was depressed in the dendritic region of chronic ethanol-treated Purkinje neurons compared with control neurons (p < 0.05, unpaired t test), whereas there was no apparent difference in the somatic region. In contrast, peak ACPD-evoked Ca2+ signals were enhanced in both the somatic and dendritic regions of withdrawn Purkinje neurons compared with control neurons. Parallel current-clamp studies showed no consistent effect of chronic ethanol treatment or ethanol withdrawal on the membrane response to ACPD. These results show that prolonged ethanol exposure and early withdrawal lead to alterations in mGluR-evoked Ca2+ signaling in cerebellar Purkinje neurons. Metabotropic GluRs in the Purkinje neuron play important roles in cerebellar development and function, suggesting that alterations of mGluR signaling pathways by ethanol may play a key role in the actions of ethanol on the developing cerebellum.

Chronic Ethanol Treatment and Withdrawal Alter ACPD-Evoked Calcium Signals in Developing Purkinje Neurons

Background: Alcohol exposure during human fetal development can result in fetal alcohol syndrome, a condition characterized by central nervous system dysfunction. Detailed studies in animal models of fetal alcohol syndrome show that the cerebellar region is particularly sensitive to alcohol exposure during early development; however, the cellular mechanisms underlying the alcohol sensitivity of the immature cerebellum are poorly understood. Methods: Primary neuronal cultures of cerebellar cells were prepared from embryonic day 20 rat pups. Cultures were exposed to ethanol (33 mM; 150 mg/100 ml) during the main period of morphological development of the Purkinje neurons, from 6 to 17 days in vitro. After the ethanol treatment, the response of Purkinje neurons to the selective metabotropic glutamate receptor (mGluR) agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD; 300 μM) was examined in parallel fura-2 Ca2+ imaging and current-clamp experiments. In an additional set of experiments, ethanol-treated cultures were allowed to withdraw from ethanol overnight before recordings were performed. Results: In Ca2+ imaging studies, the mean peak amplitude of ACPD-evoked Ca2+ signals was depressed in the dendritic region of chronic ethanol–treated Purkinje neurons compared with control neurons (p < 0.05, unpaired t test), whereas there was no apparent difference in the somatic region. In contrast, peak ACPD-evoked Ca2+ signals were enhanced in both the somatic and dendritic regions of withdrawn Purkinje neurons compared with control neurons. Parallel current-clamp studies showed no consistent effect of chronic ethanol treatment or ethanol withdrawal on the membrane response to ACPD. Conclusions: These results show that prolonged ethanol exposure and early withdrawal lead to alterations in mGluR-evoked Ca2+ signaling in cerebellar Purkinje neurons. Metabotropic GluRs in the Purkinje neuron play important roles in cerebellar development and function, suggesting that alterations of mGluR signaling pathways by ethanol may play a key role in the actions of ethanol on the developing cerebellum.

Liver development in a rat model of fetal alcohol syndrome.

The inhibitory effects of alcohol on hepatic growth in adults raises the possibility that the liver may be involved in fetal alcohol syndrome (FAS) in infants. To test this hypothesis, pregnant Sprague-Dawley rats were fed liquid diets containing either ethanol as 36% of the total calories, or were allowed ad libitum feeding of a control liquid diet (controls) throughout pregnancy. Other dams were exposed to the ethanol diet only during the first or last half of pregnancy. Pups delivered of dams exposed to the various diets (N = 40-45/group) were killed at 1, 3, 7, and 14 days of age. In addition to brain weights, crown-rump lengths, and facial features, the following parameters of liver development were documented; liver weight, liver/body weight ratio, liver histology, hepatic ornithine decarboxylase activity (ODC), hepatic protein content, and rate of hepatic DNA synthesis (as determined by [3H]thymidine incorporation). The results revealed that pups exposed to ethanol throughout pregnancy but not ad libitum control diet pups had brain weights, crown-rump lengths, and facial features in keeping with FAS. With respect to liver development, the livers in FAS pups were consistently smaller than in the control group. However, total body weights were decreased to a greater extent, such that when corrected for body weights, the smaller livers in FAS pups only became significant on day 14 of life. Liver histology was similar in the two groups with no signs of active inflammation or fibrosis. Hepatic ODC activity was also similar, indicating no impairment in polyamine synthesis. Hepatic DNA synthesis rates were decreased in FAS pups at all time intervals. Pups delivered of dams exposed to ethanol during either the first or last half of pregnancy had results comparable to those of controls. To identify the mechanism(s) responsible for these findings, a second series of experiments was performed wherein the hepatic expression of the following factors associated with liver development were documented by northern-blot analyses; growth hormone receptor (GHr), insulin-like growth factor-I (IGF-I) and -II (IGF-II) and IGF binding proteins (IGFBPs) 1, 2, 3, and 4 mRNA on gestational days 16 and 20 and postpartum days 1 and 7. In this series, a third group of pups derived from dams in whom caloric consumption was matched to that of the ethanol-fed dams (isocaloric controls) were also studied. The results revealed no consistent differences in GHr, IGF, or IGFBP mRNA expression in the three groups. In conclusion, liver development and hepatic DNA synthesis were significantly impaired in this animal model of FAS. That impairment, however, was not associated with decreases in either polyamine synthesis or disturbances in the hepatic component of the GH/IGF/IGFBP axis.

Neuronal instability: implications for Rett's syndrome

The maturational changes in the brain and spinal cord do not linearly proceed from immature in infants to mature in adults. Dendrites dynamically extend or retract as neurotrophic factors fluctuate. In certain cases mature neurons can be seen soon after birth, and in other cases immature neurons can be identified in the aged brain. Monoamine ‘neurotransmitter’; such as serotonin (5-HT), dopamine and norepinephrine appear to function as Maintenance Growth Factors since they must be present in order to produce their maturational actions. Serotonin neurons contain TRK-B receptors and are sensitive to availability of the trophic factor, BDNF. 5-HT also functions by promoting the release of the glial extension factor, S-100β. 5-HT and S-100β can provide maturational signals to a variety of neurons, in both cortical and subcortical areas, and appear to be involved in regulating the maturation and release of acetylcholine and dopamine. We have shown that activation of the 5-HT1A receptor is particularly effective in inducing growth of stunted neurons. The mechanism of action of the 5-HT1A receptor involves both a direct inhibition on c-AMP and pCREB formation in postsynaptic neurons and a release of S-100β from glial cells. Both these events are capable of stabilization and elaboration of the cytoskeleton of the neuron and inhibition of apoptosis. 5-HT1A receptors have been shown to effectively reverse stunted neurons and microencephaly produced in animal models of fetal alcohol syndrome and prenatal cocaine administration. I discuss the implications for regressive disorders such as Rett's syndrome and autism, and the feasibility of treatments with 5-HT1A agonists in children with developmental disorders.

Critical periods for the effects of alcohol exposure on learning in rats.

Critical periods for alcohol-induced deficits in spatial navigation and passive avoidance learning were investigated with a rat model of fetal alcohol syndrome. Rats were exposed to alcohol prenatally (Gestational Days 1-10 or 11-22) or postnatally (Postnatal Days 2-10) or throughout all 3 periods. Offspring were tested in either a spatial navigation or an avoidance task as juveniles or adults. As juveniles, the combined exposure group took longer to learn the spatial navigation task compared with all other groups. This effect was not seen in adults. Passive avoidance performance was not affected. These results suggest that long-term exposure to alcohol during development has adverse effects on spatial learning. The lack of differences in the short-term exposure groups implies that there may not be 1 critical period of alcohol exposure, but that the adverse effects of alcohol during development may be cumulative on some behaviors.