The emerging role of N6-methyladenine RNA methylation in metal ion metabolism and metal-induced carcinogenesis.

N6-methyladenine (m6A) is the most common and abundant internal modification in eukaryotic mRNAs, which can regulate gene expression and perform important biological tasks. Metal ions participate in nucleotide biosynthesis and repair, signal transduction, energy generation, immune defense, and other important metabolic processes. However, long-term environmental and occupational exposure to metals through food, air, soil, water, and industry can result in toxicity, serious health problems, and cancer. Recent evidence indicates dynamic and reversible m6A modification modulates various metal ion metabolism, such as iron absorption, calcium uptake and transport. In turn, environmental heavy metal can alter m6A modification by directly affecting catalytic activity and expression level of methyltransferases and demethylases, or through reactive oxygen species, eventually disrupting normal biological function and leading to diseases. Therefore, m6A RNA methylation may play a bridging role in heavy metal pollution-induced carcinogenesis. This review discusses interaction among heavy metal, m6A, and metal ions metabolism, and their regulatory mechanism, focuses on the role of m6A methylation and heavy metal pollution in cancer. Finally, the role of nutritional therapy that targeting m6A methylation to prevent metal ion metabolism disorder-induced cancer is summarized.

Characterizing the influence of gut microbiota on host tryptophan metabolism with germ-free pigs.

Intestinal microbes are closely associated with host health, depending on metabolic crosstalk between the microbiota and host. Tryptophan metabolism is one of the best examples of metabolic crosstalk between intestinal microbiota and host; however, our understanding about the influence of intestinal microbiota on host tryptophan metabolism is limited. Thus, we established germ-free (GF) pig models to systemically explore the influence of intestinal microbiota on tryptophan metabolism. Five GF pigs were kept in GF conditions throughout the experiment (GF group). Six GF pigs were transplanted with fecal microbiota from donor sows to act as control pigs. Compared with control pigs, the GF pigs had remarkable alterations in tryptophan metabolism. The differential metabolites (P < 0.05) were mainly found in the liver, circulation system and large intestine. Notably, the alteration of metabolites in tryptophan metabolism varied among organs, especially for the serotonin pathway. In GF pigs, tryptophan and kynurenine in the large intestine and 5-hydroxytryptophan in most organs were increased (P < 0.05), while metabolites in the indole pathway in most organs were decreased (P < 0.05). Collectively, our study reveals changes in tryptophan metabolism in GF pigs, highlighting the critical role of gut microbes in shaping host tryptophan metabolism.

Gut microbiota contributes to the methionine metabolism in host.

Methionine (Met) metabolism provides methyl groups for many important physiological processes and is implicated in multiple inflammatory diseases associated with the disrupted intestinal microbiota; nevertheless, whether intestinal microbiota determines Met metabolism in the host remains largely unknown. Here, we found that gut microbiota is responsible for host Met metabolism by using various animal models, including germ-free (GF) pigs and mice. Specifically, the Met levels are elevated in both GF pigs and GF mice that mainly metabolized to S-adenosine methionine (SAM) in the liver. Furthermore, antibiotic clearance experiments demonstrate that the loss of certain ampicillin- or neomycin-sensitive gut microbiota causes decreased Met in murine colon. Overall, our study suggests that gut microbiota mediates Met metabolism in the host and is a prospective target for the treatment of Met metabolism-related diseases.

Effects of Lactococcus lactis on the Intestinal Functions in Weaning Piglets.

Post-weaning diarrhea of piglets is associated with gut microbiota dysbiosis and intestinal pathogen infection. Recent studies have shown that Lactococcus lactis (L.lactis) could help suppress pathogen infection. This study aimed to investigate the effects of L.lactis on various factors related to growth and immunity in weaning piglets. The results showed that L.lactis improved the growth performance, regulated the amino acid profile (for example, increasing serum tryptophan and ileal mucosal cystine) and the intestinal GABAergic system (including inhibiting ileal gene expression of SLC6A13, GABAAρ1, π, θ, and γ1, and promoting ileal GABAAα5 expression). L.lactis also modulated intestinal immunity by promoting jejunal interleukin 17, 18, 22, ileal toll-like receptor 2, 5, 6, and myeloid differentiation primary response protein 88 gene expression while inhibiting jejunal interferon-γ and ileal interleukin 22 expressions. L.lactis highly affected the intestinal microbiota by improving the beta diversity of gut microbiota and the relative abundance of Halomonas and Shewanella. In conclusion, L.lactis improved the growth performance and regulated amino acid profiles, intestinal immunity and microbiota in weaning piglets.

Long-term outcomes and independent predictors of mortality in patients presenting to emergency departments with acute heart failure in Beijing: a multicenter cohort study with a 5-year follow-up.

BACKGROUND: Acute heart failure (AHF) is the most common disease in emergency departments (EDs). However, clinical data exploring the outcomes of patients presenting AHF in EDs are limited, especially the long-term outcomes. The purposes of this study were to describe the long-term outcomes of patients with AHF in the EDs and further analyze their prognostic factors. METHODS: This prospective, multicenter, cohort study consecutively enrolled 3335 patients with AHF who were admitted to EDs of 14 hospitals from Beijing between January 1, 2011 and September 23, 2012. Kaplan-Meier and Cox regression analysis were adopted to evaluate 5-year outcomes and associated predictors. RESULTS: The 5-year mortality and cardiovascular death rates were 55.4% and 49.6%, respectively. The median overall survival was 34 months. Independent predictors of 5-year mortality were patient age (hazard ratio [HR]: 1.027, 95 confidence interval [CI]: 1.023-1.030), body mass index (BMI) (HR: 0.971, 95% CI: 0.958-0.983), fatigue (HR: 1.127, 95% CI: 1.009-1.258), ascites (HR: 1.190, 95% CI: 1.057-1.340), hepatic jugular reflux (HR: 1.339, 95% CI: 1.140-1.572), New York Heart Association (NYHA) class III to IV (HR: 1.511, 95% CI: 1.291-1.769), heart rate (HR: 1.003, 95% CI: 1.001-1.005), diastolic blood pressure (DBP) (HR: 0.996, 95% CI: 0.993-0.999), blood urea nitrogen (BUN) (HR: 1.014, 95% CI: 1.008-1.020), B-type natriuretic peptide (BNP)/N-terminal pro-B-type natriuretic peptide (NT-proBNP) level in the third (HR: 1.426, 95% CI: 1.220-1.668) or fourth quartile (HR: 1.437, 95% CI: 1.223-1.690), serum sodium (HR: 0.980, 95% CI: 0.972-0.988), serum albumin (HR: 0.981, 95% CI: 0.971-0.992), ischemic heart diseases (HR: 1.195, 95% CI: 1.073-1.331), primary cardiomyopathy (HR: 1.382, 95% CI: 1.183-1.614), diabetes (HR: 1.118, 95% CI: 1.010-1.237), stroke (HR: 1.252, 95% CI: 1.121-1.397), and the use of diuretics (HR: 0.714, 95% CI: 0.626-0.814), ß-blockers (HR: 0.673, 95% CI: 0.588-0.769), angiotensin-converting enzyme inhibitors (ACEIs) (HR: 0.714, 95% CI: 0.604-0.845), angiotensin-II receptor blockers (ARBs) (HR: 0.790, 95% CI: 0.646-0.965), spironolactone (HR: 0.814, 95% CI: 0.663-0.999), calcium antagonists (HR: 0.624, 95% CI: 0.531-0.733), nitrates (HR: 0.715, 95% CI: 0.631-0.811), and digoxin (HR: 0.579, 95% CI: 0.465-0.721). CONCLUSIONS: The results of our study demonstrate poor 5-year outcomes of patients presenting to EDs with AHF. Age, BMI, fatigue, ascites, hepatic jugular reflux, NYHA class III to IV, heart rate, DBP, BUN, BNP/NT-proBNP level in the third or fourth quartile, serum sodium, serum albumin, ischemic heart diseases, primary cardiomyopathy, diabetes, stroke, and the use of diuretics, ß-blockers, ACEIs, ARBs, spironolactone, calcium antagonists, nitrates, and digoxin were independently associated with 5-year all-cause mortality.

Diosmetin reduces bone loss and osteoclastogenesis by regulating the expression of TRPV1 in osteoporosis rats.

BACKGROUND: Osteoporosis is a systemic skeletal disorder and occurs frequently in postmenopausal women and older men. This study aimed to examine whether diosmetin (DIO) can relieve estrogen deficiency-induced osteoporosis and to explore the underlying mechanisms of this potential effect. METHODS: Forty-nine Sprague-Dawley (SD) rats were divided into seven groups. Six groups underwent bilateral ovariectomy (OVX), while the sham group underwent ovarian exposure surgery. DIO and evodiamine were administered 3 days before surgery, and then subcutaneously every 3 days for 3 months in the following fashion: group I, DIO (100 mg/kg); group II, OVX; group III, OVX + DIO (50 mg/kg); group IV, OVX + DIO (100 mg/kg); group V, OVX + evodiamine (10 mg/kg) group; group VI, OVX + DIO (100 mg/kg) + evodiamine (10 mg/kg) group. Bone histopathological damage, bone loss, osteoclast production, and the expression level of transient receptor potential vanilloid 1 (TRPV1) were detected. RESULTS: Compared with the sham group, the expression of bone resorption-related genes, osteoclast-associated receptor (OSCAR) (1.00%±0.16% versus 4.5%±0.28%, **, P<0.01) and tartrate-resistant acid phosphatase (TRAP) (2.0%±0.6% versus 18.00±1.2%, ***, P<0.001), was increased significantly. The protein level of osteogenic marker proteins, osterix (Osx) (1.0%±0.1% versus 0.03%±0.01%, **, P<0.01) and type 1 collagen (COL1A1) (1.0%±0.13% versus 0.13%±0.05%, **, P<0.01) was decreased significantly with the increase of TRPV1 (1.0%±0.15% versus 2.89%±0.28%, **, P<0.01) protein level. Notably, DIO can alleviate some abnormal symptoms related to osteoporosis. CONCLUSIONS: DIO can relieve typical osteoporosis symptoms in an OVX osteoporosis rat model. The underlying mechanism may be associated with the downregulation of TRPV1.

[Progress in the effects of injury and regeneration of gustatory nerves on the taste functions in animals].

The sensor of the taste is the taste bud. The signals originated from the taste buds are transmitted to the central nervous system through the gustatory taste nerves. The chorda tympani nerve (innervating the taste buds of the anterior tongue) and glossopharyngeal nerve (innervating the taste buds of the posterior tongue) are the two primary gustatory nerves. The injuries of gustatory nerves cause their innervating taste buds atrophy, degenerate and disappear. The related taste function is also impaired. The impaired taste function can be restored after the gustatory nerves regeneration. The rat model of cross-regeneration of gustatory nerves is an important platform for research in the plasticity of the central nervous system. The animal behavioral responses and the electrophysiological properties of the gustatory nerves have changed a lot after the cross-regeneration of the gustatory nerves. The effects of the injury, regeneration and cross-regeneration of the gustatory nerves on the taste function in the animals will be discussed in this review. The prospective studies on the animal model of cross-regeneration of gustatory nerves are also discussed in this review. The study on the injury, regeneration and cross-regeneration of the gustatory nerves not only benefits the understanding of mechanism for neural plasticity in gustatory nervous system, but also will provide theoretical basis and new ideas for seeking methods and techniques to cure dysgeusia.

Characterization of hippocampal Cajal-Retzius cells during development in a mouse model of Alzheimer's disease (Tg2576).

Cajal-Retzius cells are reelin-secreting neurons in the marginal zone of the neocortex and hippocampus. The aim of this study was to investigate Cajal-Retzius cells in Alzheimer's disease pathology. Results revealed that the number of Cajal-Retzius cells markedly reduced with age in both wild type and in mice over-expressing the Swedish double mutant form of amyloid precursor protein 695 (transgenic (Tg) 2576 mice). Numerous reelin-positive neurons were positive for activated caspase 3 in Tg2576 mice, suggesting that Cajal-Retzius neuronal loss occurred via apoptosis in this Alzheimer's disease model. Compared with wild type, the number of Cajal-Retzius cells was significantly lower in Tg2576 mice. Western blot analysis confirmed that reelin levels were markedly lower in Tg2576 mice than in wild-type mice. The decline in Cajal-Retzius cells in Tg2576 mice was found to occur concomitantly with the onset of Alzheimer's disease amyloid pathology and related behavioral deficits. Overall, these data indicated that Cajal-Retzius cell loss occurred with the onset and development of Alzheimer's disease.

Effect of siRNA­induced inhibition of IL­6 expression in rat cerebral gliocytes on cerebral edema following traumatic brain injury.

The present study aimed to investigate the effect of RNA interference (RNAi) on the inhibition of interleukin (IL)­6 expression in rat cerebral gliocytes in vitro and rat cerebral traumatic tissues in vivo, as well as the effect of RNAi on cerebral edema. pSUPER vectors containing IL­6 small hairpin RNA (pSUPER­IL­6 1­5) were designed, constructed and transfected into C6 rat glioma cells using cationic liposomes. ELISA was used to select the plasmid with the strongest interference effect. A freefall method was used to generate a rat brain injury model and rats were randomly divided into treatment, empty plasmid and control groups (n=14/group). IL­6 levels, water content and sodium content were determined in the brain tissues at 24 and 72 h post­injury. pSUPER­IL­6 was effectively transfected into C6 cells and was found to inhibit the expression of IL­6 rather than IL­8. The pSUPER­IL­6 1 vector was most effective in inducing RNAi. In vivo, IL­6 levels were observed to be lowest in the interference group and there were statistically significant differences in water and sodium content among the experimental groups (P<0.05). RNAi was found to inhibit IL­6 expression in vivo and in vitro in rat cerebral gliocytes, and the reduction of the IL­6 levels was found to reduce post­traumatic cerebral edema.

Effects of chronic cold exposure on murine central nervous system.

Recently, cold-adaptation medicine has gotten more and more attention because of its specific significance to health care, military activities, sports performance, and so on. Although numerous studies have focused on respiratory, immune, and circulatory systems as well as skin damage upon cold exposure, the impacts on central nervous system are not well understood. This study explores the effects of chronic cold exposure on the murine central nervous system. To establish a chronic cold-exposure animal model, adult male mice from postnatal days 40-50 (P40-50) were housed at 0-4°C for 20 days. During the study period, estrogen receptors were labeled via immunohistochemistry, the dendritic spines of visual cortical pyramidal cells were labeled with DiI diolistic assay, and synaptic ultrastructure was observed by transmission electron microscopy. The results showed that cold exposure could inhibit neural proliferation significantly, with an increase of G-protein-coupled receptor 30 (GPR30) expression. Chronic cold exposure could also induce a decrease in the dendritic spines of pyramidal cells in visual cortex, along with a decrease in the number of synaptic formations. The ultrastructure of synapses after cold exposure was observed. It was found that pre- and postsynaptic membranes were fused, with a vague synaptic cleft. Furthermore, neuronal cytoplasmic and organelle swellings were also observed, along with microtubule disintegration. In conclusion, chronic cold exposure can cause structural and functional changes in the mouse central nervous system, possibly by direct participation of estrogen and its receptor, GPR30, in response to chronic cold exposure.

Subdiaphragmatic vagotomy reduces intake of sweet-tasting solutions in rats.

Studies have shown that there are strong interactions between gustatory and visceral sensations in the central nervous system when rats ingest sweet foods or solutions. To investigate the role of the subdiaphragmatic vagi in transmitting general visceral information during the process of drinking sweet-tasting solutions, we examined the effects of subdiaphragmatic vagotomy on the intake of 0.5 mol/L sucrose, 0.005 mol/L saccharin or distilled water over the course of 1 hour in rats deprived of water. Results showed no significant difference in consumption of these three solutions in vagotomized rats. However, rats in the sham-surgery group drank more saccharin solution than sucrose solution or distilled water. Moreover, the intake of distilled water was similar between vagotomized rats and sham-surgery group rats, but significantly less sucrose and saccharin were consumed by vagotomized rats compared with rats in the sham-surgery group. These findings indicate that subdiaphragmatic vagotomy reduces intake of sweet-tasting solution in rats, and suggest that vagal and extravagal inputs play a balanced role in the control of the intake of sweet-tasting solutions. They also suggest that subdiaphragmatic vagotomy eliminates the difference in hedonic perception induced by sweet-tasting solutions compared with distilled water.

Gastrointestinal bleeding after intracerebral hemorrhage: a retrospective review of 808 cases.

BACKGROUND: This study examined the incidence and risk factors for gastrointestinal (GI) bleeding after spontaneous intracerebral hemorrhage (ICH). METHODS: The available medical records of patients with ICH admitted from June 2008 to December 2009 for any episode of GI bleeding, possible precipitating factors and administration of ulcer prophylaxis were reviewed. RESULTS: The prevalence of GI bleeding was 26.7%, including 3 cases of severe GI bleeding (0.35%). Patients with GI bleeding had significantly longer hospital stay and higher in-hospital mortality compared with patients without GI bleeding. Multivariate logistic regression analyses showed that age, Glasgow Coma Scale scores, sepsis and ICH volume were independent predictors of GI bleeding. About 63.4% of patients with ICH received stress ulcer prophylaxis. CONCLUSIONS: GI bleeding occurred frequently after ICH, but severe events were rare. Age, Glasgow Coma Scale score, sepsis and ICH volume were independent predictors of GI bleeding occurring after ICH.

[Sodium nitrite induces PC12 cell differentiation].

To investigate the potential ability of the nitrite to induce neuronal differentiation of PC12 cells, cultured PC12 cells planted on matrigel in the presence or absence of sodium nitrite were employed as model, nerve growth factor (NGF) served as a positive control. After 48 h, sodium nitrite enhanced cell viability and vascular endothelial growth factor (VEGF) secretion. Same as the effect of NGF, sodium nitrite (1.4 mmol x L(-1)) treated cultures contained a greater proportion of cells bearing neurites and neurites were much longer than those found in negative control cultures (P < 0.05). Compared with the negative control, sodium nitrite (1.4 mmol x L(-1)) also upregulated the expression of VEGF mRNA (P < 0.05) and hypoxia inducible factor 1 alpha (HIF-1 alpha) or VEGF protein expression (P < 0.05) in cultures of PC12 cells. On the other hand, these effects of the sodium nitrite were likely mediated by HIF-1alpha, since their effects were antagonized by addition of HIF-1alpha inhibitor YC-1. Taken together, these results suggest that low doses of sodium nitrite could induce neurite outgrowth in PC12 cells by activating the HIF-1alpha-VEGF pathway.

The effects of prenatal alcohol exposure on the developmental retina of mice.

AIMS: Our aim is to investigate the effects of prenatal alcohol exposure (PAE) on the development of retinal bipolar and horizontal cells. METHODS: The alterations of the retinal bipolar and horizontal cells in P7, P14 and P30 mice were observed after PAE, with immunofluorescent labeling and DiI diolistic assay. RESULTS: The retinal development of filial pups was affected by PAE in a dose-dependent and long-term manner. The number of bipolar cells of alcohol groups was significantly lower than that of the control, and the dendritic receptive field of horizontal cells was also significantly smaller than those of the control groups (P < 0.01). CONCLUSION: PAE was able to cause retarded development of pup retinal neural cells.

Death receptor 5 and neuroproliferation.

Tumor necrosis factor-related apoptosis-inducing ligand or Apo2 ligand is a member of the tumor necrosis factor superfamily of cytokines that induces apoptosis upon binding to its death domain-containing transmembrane receptors, death receptors 4 and 5 (DR4, DR5). However, DR5 is also expressed in the developing CNS where it appears to play a role unrelated to apoptosis, and instead may be involved in the regulation of neurogenesis. We report on the distribution of DR5 expression in mouse hippocampus, cerebellum, and rostral migratory stream (RMS) of olfactory bulb from embryonic (E) day 16 (E16) to postnatal (P) day (P180). At E16, DR5-positive cells were distributed widely in embryonic hippocampus with strong immunostaining in the developing dentate gyrus. In newborn hippocampus, DR5-positive cells were predominantly located in proliferative zones, such as dentate gyrus, subventricular zone, and RMS. After postnatal day 7 (P7), the number of DR5-positive cells decreased, and cells with intense fluorescence were primarily restricted to the subgranular layer (SGL), although the granular cell layer showed weak fluorescence. After P30, only few DR5-positive cells were found in SGL, and mature granule cells were negative for DR5 expression. To address whether DR5 expression is a restricted to progenitor cells and newborn neurons, we performed 5-bromo-deoxyuridine labeling. We report that proliferative cells in the SGL selectively express DR5, with lower levels of expression in cells positive for doublecortin, a marker of newborn neurons. In addition, the stem cells in intestine, cerebellum, and RMS were also demonstrated to be DR5-positive. In the meantime, in cerebellum, DR5-positive cells were also positive for glial fibrillary acidic protein, a marker of proliferative Bergmann cells. We conclude that DR5 is selectively expressed by neuroprogenitor cells and newborn neurons, suggesting that the DR5 death receptor is likely to play a key role in neuroproliferation and differentiation.

Lower variability of tacrolimus trough concentration after conversion from prograf to advagraf in stable kidney transplant recipients.

BACKGROUNDS: Variability of blood trough concentration (C0) in immunosuppressant leads to rejection and graft loss after kidney transplantation. METHODS: The aim of this study is to prospectively investigate the change of within-patient variability among stable kidney transplant recipients with conversion from twice-daily Prograf to the same milligram-for-milligram daily dose of once-daily Advagraf. RESULTS: The mean age of 129 patients was 51.3±12.1 years. The conversion to Advagraf was administrated at 6.3±4.8 years after transplantation. The daily dose was changed from 4.7±2.0 mg to 4.9±2.1 mg after conversion. Only six patients increased daily dose by 16.7% to 25% to maintain target levels. The whole blood C0 of tacrolimus before conversion was 5.9±1.7 ng/mL. The mean C0 was significantly reduced after conversion to Advagraf; it was 4.9±1.5 ng/mL on the seventh day (P<0.001) and 5.4 to 5.5 ng/mL at 1 to 6 months (P<0.05). Forty-one (31.8%) patients have reduced C0 of more than 25% on the seventh day. The percent coefficient of variation of tacrolimus C0 more than 22.5% before conversion is associated with higher risk of reduced C0 after conversion (P<0.05). Compared with before conversion, less kidney transplant recipients have percent coefficient of variation more than 22.5% after conversion (3.1% vs. 17.4% with P<0.01). CONCLUSIONS: The results support that conversion from Prograf to Advagraf among kidney transplant recipient leads to a significantly lower C0 and within-patient variability of tacrolimus C0. The within-patient variability of C0 before conversion influences C0 on the sevent day after conversion to Advagraf.

High risk of renal failure in stage 3B chronic kidney disease is under-recognized in standard medical screening.

BACKGROUND: The objective of this study was to determine the risk of renal failure in patients with under-recognized chronic kidney disease (CKD) in the self-pay standard medical screening program of health management centers. METHODS: The abbreviated Modification of Diet in Renal Disease equation was used to calculate the estimated glomerular filtration rate (eGFR) of study subjects. Study subjects with eGFR less than 60 mL/min/1.73m(2) but with normal results of routine assessment, including serum creatinine, blood urea nitrogen, urinalysis and kidney ultrasound, were defined as having under-recognized CKD. Episodes of renal failure requiring dialysis within 2 years in subjects with stage 3 to stage 5 CKD were evaluated. RESULTS: A total of 15,817 subjects were recruited and 28.4% of subjects were identified by routine assessments as having a kidney problem. The prevalences of CKD 3A, 3B, 4 and 5 were 8.3%, 1.9%, 0.3% and 0.2%, respectively. All subjects with stages 4 and 5 CKD had abnormal serum creatinine levels, but 48.7% of 1,507 subjects with stage 3 CKD (stage 3A, n = 713; stage 3B, n = 21) had normal routine assessments. Subjects with under-recognized stage 3B CKD had the highest risk (20%) of developing renal failure compared to subjects with stages 3-5 CKD and abnormal results of routine assessments. CONCLUSION: Identifying subjects with CKD stage 3 by the eGFR equation, especially in stage 3B, is advantageous in detecting the risk of renal failure over the routine clinical assessment that is currently carried out by health management institutions in Taiwan.

[Effects of alcohol exposure during pregnancy on dendritic spine and synapse of visual cortex in filial mice].

The prenatal ethanol exposure induced the alterations of dendritic spine and synapse in visual cortex and their long-term effect would be investigated in mice from P0 to P30. Pregnant mice were intubated ethanol daily from E5 through the pup's birth to establish mode of prenatal alcohol abuse. The dendritic spines of pyramidal cells in visual cortex of pups were labeled with DiI diolistic assay, and the synaptic ultrastructure was observed under transmission electron microscope. Prenatal alcohol exposure was associated with a significant decrease in the number of dendritic spines of pyramidal neurons in the visual cortex and an increase in their mean length; ultrastructural changes were also observed, with decreased numbers of synaptic vesicles, narrowing of the synaptic cleft and thickening of the postsynaptic density compared to controls. Prenatal alcohol exposure is associated with long-term changes in dendritic spines and synaptic ultrastructure. The changes were dose-dependent with long term effect even at postnatal 30.

Radial glial cells and the lamination of the cerebellar cortex.

Radial glial cells are stem cells that play an important role in neuronal migration and proliferation in the developing brain. However, how radial glial cells contribute to the lamination of the cerebellar cortex is not well understood. We therefore used immunohistochemistry and BrdU labeling to follow radial glial cell differentiation, cell migration and cerebellar cortex development in mice from embryonic day 8 to postnatal day 180. We report that radial glial cells represent the stem cell population of the neuroepithelium of the neural tube, and act as progenitors for both neurons and neuroglia. In addition, radial glial cells not only give rise to the principal cells of the cerebellar cortex, the Purkinje and granule cells, but they also provide a scaffold for the migration of these cells. We conclude that radial glial cells play a pivotal role in establishing the laminar structure of the cerebellar cortex.