Neuronal Histone Methyltransferase EZH2 Regulates Neuronal Morphogenesis, Synaptic Plasticity, and Cognitive Behavior in Mice / 神经科学通报·英文版

The histone methyltransferase enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2)-mediated trimethylation of histone H3 lysine 27 (H3K27me3) regulates neural stem cell proliferation and fate specificity through silencing different gene sets in the central nervous system. Here, we explored the function of EZH2 in early post-mitotic neurons by generating a neuron-specific Ezh2 conditional knockout mouse line. The results showed that a lack of neuronal EZH2 led to delayed neuronal migration, more complex dendritic arborization, and increased dendritic spine density. Transcriptome analysis revealed that neuronal EZH2-regulated genes are related to neuronal morphogenesis. In particular, the gene encoding p21-activated kinase 3 (Pak3) was identified as a target gene suppressed by EZH2 and H3K27me3, and expression of the dominant negative Pak3 reversed Ezh2 knockout-induced higher dendritic spine density. Finally, the lack of neuronal EZH2 resulted in impaired memory behaviors in adult mice. Our results demonstrated that neuronal EZH2 acts to control multiple steps of neuronal morphogenesis during development, and has long-lasting effects on cognitive function in adult mice.

β-Catenin Deletion in Regional Neural Progenitors Leads to Congenital Hydrocephalus in Mice / 神经科学通报·英文版

Congenital hydrocephalus is a major neurological disorder with high rates of morbidity and mortality; however, the underlying cellular and molecular mechanisms remain largely unknown. Reproducible animal models mirroring both embryonic and postnatal hydrocephalus are also limited. Here, we describe a new mouse model of congenital hydrocephalus through knockout of β-catenin in Nkx2.1-expressing regional neural progenitors. Progressive ventriculomegaly and an enlarged brain were consistently observed in knockout mice from embryonic day 12.5 through to adulthood. Transcriptome profiling revealed severe dysfunctions in progenitor maintenance in the ventricular zone and therefore in cilium biogenesis after β-catenin knockout. Histological analyses also revealed an aberrant neuronal layout in both the ventral and dorsal telencephalon in hydrocephalic mice at both embryonic and postnatal stages. Thus, knockout of β-catenin in regional neural progenitors leads to congenital hydrocephalus and provides a reproducible animal model for studying pathological changes and developing therapeutic interventions for this devastating disease.

Neurodevelopmental outcomes and risk factors of premature infants at corrected gestational age 18~24 months / 中国新生儿科杂志

Objective:To study the neurodevelopmental outcomes and risk factors of premature infants with gestational age (GA) <34 weeks.Methods:From June 2016 to June 2018, premature infants with GA<34 weeks admitted to the Neonatology Department of our hospital were retrospectively reviewed. Bayley Scales of Infant DevelopmentⅡwas used to assess the neurodevelopmental outcomes at corrected GA 18~24 months. The incidence of neurodevelopmental impairment (NDI) was determined. Mental developmental index (MDI) and psychomotor developmental index (PDI) were calculated. The infants were assigned into three groups according to their MDI and PDI scores:≥85 group, 70~84 group and <70 group. Risk factors of low MDI and PDI scores were analyzed.Results:A total of 202 premature infants with GA<34 weeks were included, including 131 males (64.9%) and 71 females (35.1%). 91 cases (45.0%) developed NDI, including 77 mild NDI (38.1%) and 14 severe NDI (6.9%). Univariate analysis found that the incidences of severe asphyxia, multiple births, Grad≥3 ROP and endotracheal intubation in the MDI<70 group were higher. At corrected GA 40 weeks, 3, 6, 12 months, MDI<70 group showed less cases of head circumference >-2SD. PDI<70 group had higher incidences of intrauterine distress, maternal gestational hypertension, multiple birth, Grade 3~4 RDS, Grade 3~4 germinal matrix-intraventricular hemorrhage and tracheal intubation ( P<0.05). Logistic regression showed gestational hypertension, history of tracheal intubation and invasive ventilation were the risk factors for low PDI score ( OR=9.176, 4.547 and 3.227, P<0.05). The head circumference >-2SD at corrected age 6m was protective factor for low MDI and PDI scores ( OR=0.063 and 0.041, P<0.001). Conclusions:Preterm infants with GA<34 weeks are likely to develop severe NDI. Avoiding unnecessary tracheal intubation and invasive ventilation and improving gestational hypertension management may be beneficial to the neurodevelopmental outcomes of preterm infants.

The roles of GluN3-containing N-methyl-D-aspartate receptor in central nerve system / 浙江大学学报·医学版

The N-methyl-D-aspartate receptor (NMDAR) in central nerve system is mostly composed of GluN1 and GluN2 subunits. The classical NMDAR has been intensively studied. However, GluN3‑containing NMDAR is much less expressed and have atypical channel properties. Recently, accumulating evidences have revealed two types of GluN3‑containing NMDAR: glutamate-gated GluN1/GluN2/GluN3 NMDAR and glycine-gated GluN1/GluN3 NMDAR. The former may play important roles in regulating synapse maturation and pruning non-used synapses, and its elevated expression at the adult stage may alter synaptic reorganization in some neuropsychiatric disorders. The latter is expressed in the medial habenula and involves in control of aversion. This article reviews the recent progresses on the expression, functional properties of GluN3‑containing atypical NMDARs and the physiological and pathological relevance.

Effect of inhaled budesonide on the prevention of bronchopulmonary dysplasia in premature infants and its impact on the development of intelligence at 1 year old / 公共卫生与预防医学

Objective To evaluate potential protective effects of inhaled budesonide on bronchopulmonary dysplasia (BPD) in premature infants and its impact on the intelligence development at 1 year of age. Methods A total of 82 preterm infants admitted to the neonatal intensive care center from January 2017 to January 2018 were selected as research subjects. The enrolled subjects were divided into a study group (Budesonide) and a control group (saline) by random number table method, with 41 cases in each group. The incidence of BPD, mortality, hospitalization time, time of withdrawal and oxygenation, and complications were compared between the two groups. The patients were regularly followed up to 1 year old after discharge. The physical growth and Gesell intelligence development of the two groups were compared. Results The incidence of BPD in the study group was significantly lower than that in the control group, and the difference was statistically significant (P<0.05). There was no significant difference in mortality between the two groups. The hospitalization time, weaning and oxygenation time, and 1-week re-intubation rate in the study group were significantly lower than those in the control group (P<0.05). There was no significant difference between the two groups in the incidence of adverse reactions and physical growth at 1 year old and Gesell intelligence evaluation. Conclusion Budesonide aerosol inhalation reduced the incidence of BPD in premature infants, shortened hospitalization and weaning time, and there were no near-term and long-term adverse reactions.

Comparison of the effects of caffeine citrate administering at different time on outcome and neuro-development of premature infants / 中国小儿急救医学

Objective@#To investigate the effect of caffeine citrate administering at different time on outcome and neurodevelopment of premature infants.@*Methods@#A total of 113 preterm infants with gestational age less than 32 weeks and birth weight less than 1 500 g who were hospitalized and treated in the neonatal intensive care unit from January 2018 to June 2018 were enrolled.According to the time when caffeine citrate treatment was started, they were divided into early treatment group(≤1 days) with 53 infants and late treatment group(1 to 10 days) with 60 infants.A retrospective analysis was performed for their clinical data.The perinatal conditions, treatment process and clinical outcomes of the two groups were compared and the neurological development was followed up at 12 months old.@*Results@#Compared with the late treatment group, the early treatment group had a significantly shorter durations of mechanical ventilation time, oxygen therapy time, hospitalization days and a significantly lower incidence of bronchopulmonary dysplasia, patent ductus arteriosusand intraventricular hemorrhage or periventricular leukomalacia, and there were significant differences between two groups(P<0.05, respectively). The neonatal behavioral neurological assessment score in the early treatment group was higher than that in the late treatment group at 40 weeks of gestational age, and there was significant difference between two groups(P<0.05). The mental developmental index at 3 months of corrected age, the mental developmental index and psychomotor developmental index at 12 months were significantly better in the early treatment group than those in the late treatment group, and there were significant differences between two groups(P<0.05, respectively).@*Conclusion@#Early use of caffeine citrate can improve the outcome of premature infants and improve the prognosis of nervous system.

Lipids: Role in Embryonic Development (Review)

Aims: We propose to briefly review the specific role of lipids in embryonic structures development. Results: Lipids are organic substances insoluble in water, divided into several classes, such as fatty acids, glycolipids, phospholipids, ceramides, sphingolipids, and stereo-lipids. They participate in processes of cellular metabolism and embryonic development which are associated with signalling, proliferation and cell migration. They act in developmental processes such as calcification and bone mineralization, pulmonary maturity, cellular differentiation, and neural survival, epithelial cells polarization and muscle formation, in which phospholipids as a major group, work more regularly. Lipids during embryonic development work directly as transport molecules or cell markers. In addition to an imbalance in its enzymatic and protein precursors (such as choline kinase), lipids can increase or decrease lipid concentration in cells, prevent its biotransformation, or affect its synergy with other molecules, leading to failures in the formation of organs such as the heart, brain, and bones. This aims to further the understanding of these processes and highlight its feasibility for future clinical applications. Conclusion: Lipids maintain cell membrane integrity in blastocysts, transport calcium to nerve and bone cells, facilitate neural apoptosis, and promote pulmonary maturation. These results aid in the understanding and prediction of alterations in lipidic metabolic syndromes in several pathological disorders during organ development.

De Novo and Inherited SETD1A Variants in Early-onset Epilepsy / 神经科学通报·英文版

Early-onset epilepsy is a neurological abnormality in childhood, and it is especially common in the first 2 years after birth. Seizures in early life mostly result from structural or metabolic disorders in the brain, and the genetic causes of idiopathic seizures have been extensively investigated. In this study, we identified four missense mutations in the SETD1A gene (SET domain-containing 1A, histone lysine methyltransferase): three de novo mutations in three individuals and one inherited mutation in a four-generation family. Whole-exome sequencing indicated that all four of these mutations were responsible for the seizures. Mutations of SETD1A have been implicated in schizophrenia and developmental disorders, so we examined the role of the four mutations (R913C, Q269R, G1369R, and R1392H) in neural development. We found that their expression in mouse primary cortical neurons affected excitatory synapse development. Moreover, expression of the R913C mutation also affected the migration of cortical neurons in the mouse brain. We further identified two common genes (Neurl4 and Usp39) affected by mutations of SETD1A. These results suggested that the mutations of SETD1A play a fundamental role in abnormal synaptic function and the development of neurons, so they may be pathogenic factors for neurodevelopmental disorders.

Longitudinal study of early neural development in premature infants with different gestational age and birth weight / 临床儿科杂志

Objective To investigate the trend of early neural development in premature infants. Methods At the age of 12 months and 24 months, Bayley Scales of Infant Development were used to assess the mental development index (MDI) and the psychomotor development index (PDI) in preterm (corrected age) and full-term infants. Results At 12 months, there was no significant difference in corrected age PDI scores among different gestational age groups (<32 , 32–33+6 and 34–36+6 weeks) (P=0.820). The actual age MDI and PDI scores of full-term infants and premature infants in 34~36+6 weeks group were significantly higher than those of premature infants in <32 and 32-33+6 weeks groups, and the PDI score of full-term infants was significantly higher than that of premature infants in 34-36+6 weeks group (P<0.05). There was no significant difference in actual age PDI scores among different birth weight groups (P=0.166). The actual age MDI and PDI of full-term infants and premature infants in birth weight≥2500 g group were significantly higher than those of premature infants in <1500 g, 1500~1999 g and 2000~2499 g groups (P<0.05). At 24 months, the actual age MDI scores of full-term infants were significantly higher than those of premature infants in different gestational age and birth weight groups (P<0.05). The actual age MDI curve of premature infants in birth weight <1500g group showed a downward trend, while the actual age PDI curve showed a significant upward trend. Conclusion The neurodevelopment of preterm infants at the corrected age of 12 and 24 months reaches the level of full-term infants.

Gut microbiota and neonate neural development / 国际儿科学杂志

Gut microbiota may be important to human health.The early colonization of gut microbiota will affect the growth and development of infants.The microbiome-gut-brain axis connects the gut microbiota to the brain,providing a communication bridge for the gut microbiota and the central nervous system,and develops in parallel with the newborn central nervous system. Gut microbiota may affect neonate neural development through metabolism,immunity,vagus nerve and neuroendocrine.Gut microbiota may also affect the permeability and integrity of neonatal blood-brain barriers by regulating the expression of tightly linked protein. In recent years,the research of gut microbiota that may regulate neonate neural development is still in its early stage,but gradually becomes a hot research topic.

Progress in microglia cell development and its function in central nervous system / 中国药理学与毒理学杂志

Microglia are a type of immune cells and widely distributed in the central nervous system(CNS), accounting for about 5% to 20% of the total number of glial cells. Microglia were first identified by Hortega using the silver carbonate method.It is believed that microglia originate from the mesoderm and invade the brain during the formation of blood vessels in the late embryonic development.Recent research shows that microglia are derived from yolk sac-derived macrophages. As a resident immune cell of the CNS,microglia belong to the monocyte-macrophage cell line and are an important immuno-logical defense against the invasion of pathogens. The resting microglia play a role in monitoring the nervous system to maintain the homeostasis.The activated microglia play a role in phagocytosis of cell debris and have neuroprotective and neurotoxic dual roles under different pathological conditions by secreting different cytokines.

SoxD Transcription Factors: Multifaceted Players of Neural Development

SoxD transcription factor subfamily includes three members, Sox5, Sox6, and Sox13. Like other Sox genes, they contain the High-Mobility-Group (HMG) box as the DNA binding domain but in addition feature the subgroup-specific leucine zipper motif. SoxD genes are expressed in diverse cell types in multiple organs during embryogenesis and in adulthood. Among the cells expressing them are those present in the developing nervous system including neural stem (or progenitor) cells as well as differentiating neurons and oligodendrocytes. SoxD transcription factors do not contain distinct activator or repressor domain, and they are believed to function in modulation of other transcription factors in promoter- specific manners. This brief review article will attempt to summarize the latest studies on the function of SoxD genes in embryogenesis with a particular emphasis on the regulation of neural development.

The clinical observation of the effects of maternal serum vitamin D levels on the developing nervous system in infants / 重庆医学

Objective To investigate the effect of maternal serum vitamin D (VD)levels on the developing nervous system in in-fants.Methods A total of 1 012 pregnant women's serum VD levels of early pregnancy were given the right amount of VD supple-mentation according to the results.They were divided into 3 groups (normal,deficiency and insufficiency group)according to the third trimester VD levels;and their infants 6-8 months were tested on the developmental quotient (DQ),mental index (MI)and other neurological development index by the Developmental Screening Test for child under six(DST).Results There were up to 94.17% of pregnant women in early pregnancy had severe VD deficiency,the average levels was (16.21 ± 7.54)ng/mL;Although VD levels was increased after supplements,there were 46.25% of pregnant women still deficient in VD.The average DQ score of 1 020 infants was 92.67±16.45 and M1 score was 97.53±17.04,which accorded with normal distribution.The rate of the infants born by mothers who had the normal VD levels were superior to those with VD deficiency and insufficiency on the quotients of out-standing and smart,and there was a significant difference between them(P 0.05).The level of VD was positively correlated with DQ and MI,and the correlation coefficients are 0.63 and 0.2(slightly correlated),respectively.Conclusion It should be pay more attention to monitoring the VD levels of the pregnant women during the pregnancy,and for lack should be promptly added.

Influence of cardiopulmonary bypass on neurodevelopmental disorder in congenital heart disease children before and after operation / 中华实用儿科临床杂志

With the advances of medical management and surgical techniques during cardiopulmonary bypass,children with congenital heart disease are increasingly surviving to adulthood.Research into their neurodevelopmental outcomes in the past 20 years had revealed sobering realizations about the adverse impact on the quality of life of these surgical survivors.A multitude of factors contribute to the incidence and severity of neurodevelopmental abnormalities and can be separated into preoperative,intraoperative,and postoperative events,in addition to genetic contributions and socioeconomic factors.This article highlight some of current understanding of these protean factors.Understanding should lead to modification of current techniques and management strategies,all with the ultimate goal of improving patients' quality of life.

Differential Expression Levels of Synaptophysin through Developmental Stages in Cerebral Cortices of Mouse Brain / 체질인류학회지

It is well known that differentiation and growth of central nervous system are accomplished through relatively early stages of development. The formation of neural synapse indicates beginning of electrical signaling between neurons, so that may be a critical step in the differentiation of neurons as well as the development and growth of central nervous system. The purpose of this study was to investigate the differential expression levels and patterns of synaptic marker (synaptophysin) between superficial and deep layers of cerebral cortex according to the developmental stages. We introduced immunofluorescence staining of synaptophysin combined with densitometric analysis for the morphological quantification. The intensities of synaptophysin immuno-reactivities in deep layers of cerebral cortices were significantly higher compared to superficial layers in cerebral cortices of embryonic and neonatal mice. The significant increase of synaptophysin expression in the deep layer of cerebral cortex was mainly confined to the embryonic stage. As the expression of synaptophysin gradually decrease thereafter, the difference of expression level between superficial and deep layers could not find in the adult mice. From this study, we could confirm indirectly through synaptophysin that synaptogenic activities in the deep layer of cerebral cortex shows unique pattern especially during the early stages of brain development. Results from this study will be helpful for understanding different patterns of synaptogenesis among the various regions of developing brain.

Differential Expression Levels of Synaptophysin through Developmental Stages in Cerebral Cortices of Mouse Brain / 체질인류학회지

It is well known that differentiation and growth of central nervous system are accomplished through relatively early stages of development. The formation of neural synapse indicates beginning of electrical signaling between neurons, so that may be a critical step in the differentiation of neurons as well as the development and growth of central nervous system. The purpose of this study was to investigate the differential expression levels and patterns of synaptic marker (synaptophysin) between superficial and deep layers of cerebral cortex according to the developmental stages. We introduced immunofluorescence staining of synaptophysin combined with densitometric analysis for the morphological quantification. The intensities of synaptophysin immuno-reactivities in deep layers of cerebral cortices were significantly higher compared to superficial layers in cerebral cortices of embryonic and neonatal mice. The significant increase of synaptophysin expression in the deep layer of cerebral cortex was mainly confined to the embryonic stage. As the expression of synaptophysin gradually decrease thereafter, the difference of expression level between superficial and deep layers could not find in the adult mice. From this study, we could confirm indirectly through synaptophysin that synaptogenic activities in the deep layer of cerebral cortex shows unique pattern especially during the early stages of brain development. Results from this study will be helpful for understanding different patterns of synaptogenesis among the various regions of developing brain.

Treatment with levothyroxine in early maternal subclinical hypothyroidism may improve the neural development of the progeny / 中华内分泌代谢杂志

Objective To investigate the effect of treatment with levothyroxine in early maternal subclinical hypothyroidism (SCH) on the neural development of the progeny. Methods 75 thyroidectomized female Wistar rats were divided randomly into groups of hypothyroidism (CH), SCH, SCH treated with levothyroxine at embryonic day 10 (E10), E13, and E17. There were 15 sham operated controls. Body weight,thyroid function, and the development of progeny by morris water maze, immunohistochemistry, and Nissl's staining of progeny were made. Results Pups from SCH or CH group had significantly lower body weight than euthyroid group ( P＜0. 05 ). Pups from E10, E13 or E17 groups had normal body weight compared to pups of control (P＞0.05). The levels of TSH and total T4( TT4 ) of all pups were normal. The mean latencies were longer in pups from CH, SCH, and E17 group than the control (P＜0.05). The mean escape latencies did not differ between the control and E10 group pups and between the control and E13 pups (P＞0.05). There were changes in the cytoarchitecture of the barrel cortex and of the hippocampus ( toluidine blue-stained sections) in CH, SCH, and E17 pups. The barrel cortex of E10 or E13 pups was similar to that of control pups. The distribution of BrdUlabeled cells was more widespread in CH, SCH, and E17 pups than in control, E10, and E13 progeny.Conclusion Maternal SCH disturbs learning and memory performances, cytoarchitecture and cell migration of the pups. Treatment with levothyroxine in early maternal SCH before E13 improves the cell migration in the developing brain of the progeny.

Progress of Caveolin and Its Role in Brain / 生物化学与生物物理进展

Caveolins are a family of plasmalemmal vesicles caveolae-associated integral membrane proteins and a marker protein of caveolae involved in the formation and localization that associated with vesicular transport, cellular cholesterol homeostasis and signal transduction. Recent years, strong experimental evidences indicated that caveolins play a pivotal role in the brain function such as neural development, synaptic plasticity and neurodegenerative diseases. Recent progress on studies of the structure and functions of caveolins was simply summarized. The regulatory role of caveolins in the brain functions has been reviewed and expected.

EFFECTS OF GESTATIONAL TOBACOO AND ALCOHOL EXPOSURE ON STATURE AND NEURAL DEVELOPMENT OF OFFSPRING IN MICE / 营养学报

Objective: To investigate the effect of prenatal tobacco and alcohol exposure on stature and neural development of offspring. Methods: Female mice were exposed to tobacco smoke and alcohol drink from D6 of pregnancy to parturition. The early physical development, neurobehavioral and antioxidative functions were measured in offspring mice. Results: Compared with control, offspring subjected to prenatal exposure showed significant reduced body and organ weights as well as reduced gestational body weight gain. It also resulted in remarkable prolonged neonatal reflexes and reduced motive, coordinative and locomotor activities. Step-down and Y-maze tests revealed marked destroyed memory and learning ability. Futhermore, MDA in offspring brain cytosol and mitochondria increased significantly and the activities of SOD, GSH-Px, CAT and GST were decreased. Conclusion: Prenatal tobacco and alcohol exposures interfere with the early physical and neural development in mice, probably related to decreased antioxidative functions.

Roles of MMP-2 and MMP-9 in the central nervous system / 医学研究生学报

The matrix metalloproteinases(MMP) are important enzymes that regulate developmental processes,maintain normal physiology in adulthood and have reparative roles in specific stages after an insult to the nervous system.Conversely,the concordant presence and significant up-regulation of several MMP members in virtually all neurological conditions result in pathological lesions.Thus,the MMPs have double functions,capable of mediating repair and recovery on the one hand and being involved in producing injury on the other.This article highlights the beneficial roles of MMP-2 and MMP-9 in normal and reparative processes within the nervous system and discusses the detriments of both encountered in spinal cord injury and central nervous system cancers,and we also review the availability of MMP inhibitors for clinical use.