Microbial necromass carbon in estuarine tidal wetlands of China: Influencing factors and environmental implication.

Microbial necromass is an important component of the stable soil organic carbon (SOC) pool. However, little is known about the spatial and seasonal patterns of soil microbial necromass and their influencing environmental factors in estuarine tidal wetlands. In the present study, amino sugars (ASs) as biomarkers of microbial necromass were investigated along the estuarine tidal wetlands of China. Microbial necromass carbon (C) contents were in the range of 1.2-6.7 mg g-1 (3.6 ± 2.2 mg g-1, n = 41) and 0.5-4.4 mg g-1 (2.3 ± 1.5 mg g-1, n = 41), which accounted for 17.3-66.5 % (44.8 % ± 16.8 %) and 8.9-45.0 % (31.0 % ± 13.7 %) of the SOC pool in the dry (March to April) and wet (August to September) seasons, respectively. At all sampling sites, fungal necromass C predominated over bacterial necromass C as a component of microbial necromass C. Compared to bacterial necromass C, fungal necromass C showed a stronger connection with ferrous oxides (Fe2+) and total Fe concentrations. Both fungal and bacterial necromass C contents revealed large spatial heterogeneity and declined in the estuarine tidal wetlands with the increase in latitude. Statistical analyses showed that the increases in salinity and pH in the estuarine tidal wetlands suppressed the accumulation of soil microbial necromass C.

Methamphetamine Exposure in Adolescent Impairs Memory of Mice in Adulthood Accompanied by Changes in Neuroplasticity in the Dorsal Hippocampus.

Methamphetamine (METH) has been shown to alter learning and memory by affecting the neuroplasticity of the dorsal hippocampus, a key structure that undergoes extensive remodeling during adolescence. In this study, we investigated whether mid-to-late adolescent exposure to METH leads to long-lasting memory impairment. To do this, adolescents (35-48 postnatal days) were exposed to different doses of METH for 14 days and then evaluated by the Morris water maze (MWM), new object recognition test (NORT), and the Y-maze, to investigate the learning and memory abilities of mice in their adolescence and adulthood, respectively. We also detected the mRNA levels of genes associated with neuroplasticity in the dorsal hippocampus. The synaptic ultrastructure and the number of neurons and astrocytes in the dorsal hippocampus were also determined by transmission electron microscopy (TEM) and immunofluorescence (IF). Exposure to METH in mid-to-late adolescence impaired spatial memory retrieval ability and the long-term recognition memory of mice in their adulthood, but not in their adolescence. Of note, the impairment of memory capacity in adulthood was accompanied by molecular and structural changes in synapses in the dorsal hippocampus. Our results indicate that mice exposed to METH in mid-to-late adolescence have impaired memory ability in their adulthood; this may be the result of abnormal changes in the structural plasticity of the dorsal hippocampus; the causal relationship between changes in synaptic structural plasticity and memory impairment needs to be further confirmed. In summary, our study provides evidence for the detrimental consequences of adolescent addiction and the prevention of adolescent drug abuse.

Medial prefrontal cortex Notch1 signalling mediates methamphetamine-induced psychosis via Hes1-dependent suppression of GABAB1 receptor expression.

Methamphetamine (METH), a widely abused stimulant drug, induces psychosis in approximately half of abusers; this effect is becoming a major concern for society. Although the Notch1 signalling pathway has been shown to play a part in the pathogenesis of some psychiatric disorders, its role in METH-induced psychosis (MIP) is still unknown. Here, the METH-induced locomotor sensitization model in rodents is considered to represent the underlying neurochemical changes driving psychoses. We found that the Notch1 signalling was downregulated in the medial prefrontal cortex (mPFC) in sensitized mice. Direct genetic and pharmacological manipulations of Notch1 signalling bidirectionally altered METH-induced locomotor sensitization and other MIP-related behaviours through governing neuronal activity in the mPFC. Moreover, Notch1 signalling negatively regulated GABAB1 receptor expression in the mPFC of METH-sensitized mice through Hes1, a transcriptional repressor in Notch1 signalling. Further, we show that Hes1 can directly bind to the GABAB1 receptor promoter. Notably, pharmacological regulation of the GABAB receptor in the mPFC reversed the changes in METH-induced locomotor sensitization caused by the dysfunction of Notch1 signalling. Together, our findings uncover a previously unrecognised Notch1-Hes1-GABAB1 receptor-dependent mechanism involved in regulating mPFC neuronal activity and behavioural phenotypes in MIP. Our work provides mechanistic insight into the aetiology and pathophysiology of MIP.

Knockout of Dopamine D3 Receptor Gene Blocked Methamphetamine-Induced Distinct Changes of Dopaminergic and Glutamatergic Synapse in the Nucleus Accumbens Shell of Mice.

Structural plasticity changes in the brain are thought to underlie, at least partially, drug-induced persistent changes in behavior. Our previous study reported that increased synaptic density in the nucleus accumbens shell (NAcsh) correlates with and may contribute to behavioral sensitization induced by methamphetamine (METH). However, the distinct changes of dopaminergic and glutamatergic synapses and the modulating effects of dopamine D3 receptor remain unclear. In the current study, we used immunohistochemistry electron-microscopy and immunofluorescence to detect the changes of dopamine D1, D2, and glutamate NR2B-positive synapses and cells in the NAcsh of METH-sensitized wild type (WT) and knockout of dopamine D3 receptor gene (D3-/-) mice. We found that METH induced long-term behavioral sensitization in WT mice, which was accompanied by an increased number and rate of dopamine D1 receptor-positive synapses and cells, as well as glutamate NR2B-positive synapses and cells. In contrast, the number and rate of dopamine D2 receptor-positive synapses and cells were significantly decreased in the NAcsh of METH-sensitized WT mice. D3-/- mice exhibited attenuated acute locomotor responses and behavioral sensitization to METH compared with WT mice. Moreover, the knockout of dopamine D3 receptor gene inhibited METH-induced changes of dopaminergic and glutamatergic synapses in the NAcsh of METH-sensitized mice. Taken together, our results suggest that METH induced distinct changes of dopaminergic and glutamatergic synapses and cells in the NAcsh of mice, which was blocked by the knockout of dopamine D3 receptor gene, and may contribute to, at least partially, METH-induced behavior sensitization as well as the modulating effect of the dopamine D3 receptor.

ZIF-67 Derived Co2VO4 Hollow Nanocubes for High Performance Asymmetric Supercapacitors.

In this work, a new type of Co2VO4 hollow nanocube (CoVO-HNC) was synthesized through an ion exchange process using ZIF-67 nanocubes as a template. The hollow nanocubic structure of the CoVO-HNC provides an abundance of redox sites and shortens the ion/electron diffusion path. As the electrode material of supercapacitors, the specific capacitance of CoVO-HNC is 427.64 F g-1 at 1.0 A g-1. Furthermore, an asymmetric supercapacitor (ASC) was assembled using CoVO-HNC and activated carbon (AC) as electrodes. The ASC device attains an energy density of 25.28 Wh kg-1 at a high-power density of 801.24 W kg-1, with 78% capacitance retention after 10,000 cycles at 10 A g-1.

Treatment Strategies for Ventricular Septal Rupture After Myocardial Infarction: A Single-Center Experience.

Objective: To analyze treatment strategies, prognosis, and related risk factors of patients with postinfarction ventricular septal rupture, as well as the impact of timing of surgical intervention. Methods: A total of 23 patients diagnosed with postinfarction ventricular septal rupture who were non-selectively admitted to Shanxi Provincial Cardiovascular Hospital between October 2017 and August 2021 were included in this study. The relevant clinical data, operation-related conditions, and follow-up data were summarized for all patients. The Kaplan-Meier method and log-rank test were used for the cumulative incidence of unadjusted mortality in patients with different treatment methods. Multivariate logistic regression was used to evaluate the independent risk factors for in-hospital patient mortality. Results: The mean age of the study patients was 64.43 ± 7.54 years, 12(52.2%) were females. There was a significant difference in terms of postoperative residual shunt between the surgical and interventional closure groups (5.9 vs. 100%, respectively; P < 0.001). The overall in-hospital mortality rate was 21.7%; however, even though the surgical group had a lower mortality rate than the interventional closure group (17.6 vs. 33%, respectively), this difference was not statistically significant (P = 0.576). Univariate analysis showed that in-hospital survival group patients were significantly younger than in-hospital death group patients (62.50 ± 6.53 vs. 71.40 ± 7.37 years, respectively; P = 0.016), and that women had a significantly higher in-hospital mortality rate than men (P = 0.037). The average postoperative follow-up time was 18.11 ± 13.92 months; as of the end of the study all 14 patients in the surgical group were alive, Two out of four patients survived and two patients died after interventional closure. Univariate analysis showed that interventional closure was a risk factor for long-term death (P < 0.05). Conclusion: Surgical operation is the most effective treatment for patients with postinfarction ventricular septal rupture; however, the best timing of the operation should be based on the patient's condition and comprehensively determined through real-time evaluation and monitoring. We believe that delaying the operation time as much as possible when the patient's condition permits can reduce postoperative mortality. Interventional closure can be used as a supplementary or bridge treatment for surgical procedures.

The discrepancy of aromatase expression in epicardial adipose tissue between CHD and non-CHD patients.

OBJECTIVES: Epicardial adipose tissue (EAT) aromatase converts androstenedione and other adrenal androgens into oestrogens. The locally produced oestradiol (E2) may have cardiovascular protective effects. Little is known about the relationship between EAT aromatase level and coronary heart disease (CHD). Here, we compared EAT aromatase levels in CHD versus non-CHD patients and assessed the relationship between EAT aromatase levels and lesion degree in the coronary arteries. METHODS: EAT and blood specimens were obtained from patients undergoing thoracotomy prior to cardiopulmonary bypass. Serum E2 levels were obtained from our hospital laboratory. EAT aromatase expression was determined by RT-qPCR and ELISA assays. All patients underwent coronary angiography and the level of coronary lesions was evaluated with the SYNTAX score. RESULTS: Compared with non-CHD patients, CHD patients had lower EAT aromatase mRNA and protein levels. In the CHD patients, EAT aromatase and oestrogen levels negatively correlated with the severity of coronary artery disease. CONCLUSIONS: Our data revealed that reduced EAT aromatase levels correlated with coronary atherosclerotic lesions. Reduced EAT aromatase protein levels may aggravate the severity of atherosclerosis. Future studies should investigate the mechanisms regulating aromatase expression in epicardial fat.

Correction to: Rescue of Methyl-CpG Binding Protein 2 Dysfunction-induced Defects in Newborn Neurons by Pentobarbital.

C.-H. Yang's appeared incorrectly on the original publication of this article.

Ago2 and Dicer1 are involved in METH-induced locomotor sensitization in mice via biogenesis of miRNA.

microRNA (miRNA) play important roles in drug addiction and act as a post-transcriptional regulator of gene expression. We previously reported extensive downregulation of miRNAs in the nucleus accumbens (NAc) of methamphetamine (METH)-sensitized mice. However, the regulatory mechanism of this METH-induced downregulation of miRNAs has yet to be elucidated. Thus, we examined METH-induced changes in the expression of miRNAs and their precursors, as well as the expression levels of mRNA and the proteins involved in miRNA biogenesis such as Dicer1 and Ago2, in the nucleus accumbens of METH-induced locomotor sensitized mice. miRNAs and Ago2 were significantly downregulated, while the expression of miRNA precursors remained unchanged or upregulated, which suggests that the downregulation of miRNAs was likely due to a reduction in Ago2-mediated splicing but unlikely to be regulated at the transcription level. Interestingly, the expression level of Dicer1, which is a potential target of METH-induced decreased miRNAs, such as miR-124, miR-212 and miR-29b, was significantly increased. In conclusion, this study indicates that miRNA biogenesis (such as Ago2 and Dicer1) and their miRNA products may have a role in the development of METH addiction.

PD-linked CHCHD2 mutations impair CHCHD10 and MICOS complex leading to mitochondria dysfunction.

Coiled-coil-helix-coiled-coil-helix domain containing protein 2 (CHCHD2) mutations were linked with autosomal dominant Parkinson's disease (PD) and recently, Alzheimer's disease/frontotemporal dementia. In the current study, we generated isogenic human embryonic stem cell (hESC) lines harboring PD-associated CHCHD2 mutation R145Q or Q126X via clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) method, aiming to unravel pathophysiologic mechanism and seek potential intervention strategy against CHCHD2 mutant-caused defects. By engaging super-resolution microscopy, we identified a physical proximity and similar distribution pattern of CHCHD2 along mitochondria with mitochondrial contact site and cristae organizing system (MICOS), a large protein complex maintaining mitochondria cristae. Isogenic hESCs and differentiated neural progenitor cells (NPCs) harboring CHCHD2 R145Q or Q126X mutation showed impaired mitochondria function, reduced CHCHD2 and MICOS components and exhibited nearly hollow mitochondria with reduced cristae. Furthermore, PD-linked CHCHD2 mutations lost their interaction with coiled-coil-helix-coiled-coil-helix domain containing protein 10 (CHCHD10), while transient knockdown of either CHCHD2 or CHCHD10 reduced MICOS and mitochondria cristae. Importantly, a specific mitochondria-targeted peptide, Elamipretide/MTP-131, now tested in phase 3 clinical trials for mitochondrial diseases, was found to enhance CHCHD2 with MICOS and mitochondria oxidative phosphorylation enzymes in isogenic NPCs harboring heterozygous R145Q, suggesting that Elamipretide is able to attenuate CHCHD2 R145Q-induced mitochondria dysfunction. Taken together, our results suggested CHCHD2-CHCHD10 complex may be a novel therapeutic target for PD and related neurodegenerative disorders, and Elamipretide may benefit CHCHD2 mutation-linked PD.

Choline Rescues Behavioural Deficits in a Mouse Model of Rett Syndrome by Modulating Neuronal Plasticity.

Rett syndrome (RTT) is a postnatal neurodevelopmental disorder that primarily affects girls, with 95% of RTT cases resulting from mutations in the methyl-CpG-binding protein 2 (MECP2) gene. Choline, a dietary micronutrient found in most foods, has been shown to be important for brain development and function. However, the exact effects and mechanisms are still unknown. We found that 13 mg/day (1.7 × required daily intake) of postnatal choline treatment to Mecp2-conditional knockout mice rescued not only deficits in motor coordination, but also their anxiety-like behaviour and reduced social preference. Cortical neurons in the brains of Mecp2-conditional knockout mice supplemented with choline showed enhanced neuronal morphology and increased density of dendritic spines. Modelling RTT in vitro by knocking down the expression of the MeCP2 protein with shRNA, we found that choline supplementation to MeCP2-knockdown neurons increased their soma sizes and the complexity of their dendritic arbors. Rescue of the morphological defects could lead to enhanced neurotransmission, as suggested by an observed trend of increased expression of synaptic proteins and restored miniature excitatory postsynaptic current frequency in choline-supplemented MeCP2-knockdown neurons. Through the use of specific inhibitors targeting each of the known physiological pathways of choline, synthesis of phosphatidylcholine from choline was found to be essential in bringing about the changes seen in the choline-supplemented MeCP2-knockdown neurons. Taken together, these data reveal a role of choline in modulating neuronal plasticity, possibly leading to behavioural changes, and hence, a potential for using choline to treat RTT.

Maternal methamphetamine exposure causes cognitive impairment and alteration of neurodevelopment-related genes in adult offspring mice.

Prenatal drug exposure altered cognitive function in individuals, and may also impact their offspring's susceptibility to cognitive impairment. The high incidence of methamphetamine (METH) abuse among adolescents and women of childbearing age elevates the importance to determine the influence of maternal METH exposure on cognitive functions in the descendants. We hypothesized that maternal METH exposure affects cognitive behavior in offspring mice by disrupting gene expression associated with neural development. Here, female C57BL/6 mice were exposed to intermittent escalating doses of METH or saline from adolescence to adulthood, and then continued through pregnancy. Interestingly, male but not female offspring exhibited impaired short-term recognition memory and long-term spatial memory retention in novel object recognition and Morris water maze test respectively. Additionally, maternal METH exposure altered neurodevelopmental genes in both male and female offspring, and 12 differentially expressed genes between male and female were observed in the HPC and NAc regions. These differentially expressed genes are involved in neurogenesis, axon guidance, neuron migration and synapse of neural development circuits. Our observations suggest that maternal METH exposure induced differential expression patterns of neurodevelopment-related genes in the HPC and NAc of male and female mice, which may underlie the different cognitive behavior phenotypes in both genders.

Human Rett-derived neuronal progenitor cells in 3D graphene scaffold as an in vitro platform to study the effect of electrical stimulation on neuronal differentiation.

Studies of electrical stimulation therapies for the treatment of neurological disorders, such as deep brain stimulation, have almost exclusively been performed using animal-models. However, because animal-models can only approximate human brain disorders, these studies should be supplemented with an in vitro human cell-culture based model to substantiate the results of animal-based studies and further investigate therapeutic benefit in humans. This study presents a novel approach to analyze the effect of electrical stimulation on the neurogenesis of patient-induced pluripotent stem cell (iPSC) derived neural progenitor cell (NPC) lines, in vitro using a 3D graphene scaffold system. The iPSC-derived hNPCs used to demonstrate the system were collected from patients with Rett syndrome, a debilitating neurodevelopmental disorder. The graphene scaffold readily supported both the wild-type and Rett NPCs. Electrical stimulation parameters were optimized to accommodate both wild-type and Rett cells. Increased cell maturation and improvements in cell morphology of the Rett cells was observed after electrical stimulation. The results of the pilot study of electrical stimulation to enhance Rett NPCs neurogenesis were promising and support further investigation of the therapy. Overall, this system provides a valuable tool to study electrical stimulation as a potential therapy for neurological disorders using patient-specific cells.

HoxC5 and miR-615-3p target newly evolved genomic regions to repress hTERT and inhibit tumorigenesis.

The repression of telomerase activity during cellular differentiation promotes replicative aging and functions as a physiological barrier for tumorigenesis in long-lived mammals, including humans. However, the underlying mechanisms remain largely unclear. Here we describe how miR-615-3p represses hTERT expression. mir-615-3p is located in an intron of the HOXC5 gene, a member of the highly conserved homeobox family of transcription factors controlling embryogenesis and development. Unexpectedly, we found that HoxC5 also represses hTERT expression by disrupting the long-range interaction between hTERT promoter and its distal enhancer. The 3'UTR of hTERT and its upstream enhancer region are well conserved in long-lived primates. Both mir-615-3p and HOXC5 are activated upon differentiation, which constitute a feed-forward loop that coordinates transcriptional and post-transcriptional repression of hTERT during cellular differentiation. Deregulation of HOXC5 and mir-615-3p expression may contribute to the activation of hTERT in human cancers.

A 3D neurovascular microfluidic model consisting of neurons, astrocytes and cerebral endothelial cells as a blood-brain barrier.

The neurovascular unit is a complex, interdependent system composed of neurons and neural supporting cells, such as astrocytes, as well as cells that comprise the vascular system including endothelial cells, pericytes, and smooth muscle cells. Each cell type in the neurovascular unit plays an essential role, either in transmitting and processing neural signals or in maintaining the appropriate microenvironmental conditions for healthy neural function. In vitro neurovascular models can be useful for understanding the different roles and functions of the cells composing the neurovascular unit, as well as for assessing the effects on neural function of therapeutic compounds after crossing the endothelial barrier. Here, we report a novel three-dimensional neurovascular microfluidic model consisting of primary rat astrocytes and neurons together with human cerebral microvascular endothelial cells. These three cell types in our neurovascular chip (NVC) show distinct cell type-specific morphological characteristics and functional properties. In particular, morphological and functional analysis of neurons enables quantitative assessment of neuronal responses, while human cerebral endothelial cells form monolayers with size-selective permeability similar to existing in vitro blood-brain barrier (BBB) models.

mRNA changes in nucleus accumbens related to methamphetamine addiction in mice.

Methamphetamine (METH) is a highly addictive psychostimulant that elicits aberrant changes in the expression of microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) in the nucleus accumbens of mice, indicating a potential role of METH in post-transcriptional regulations. To decipher the potential consequences of these post-transcriptional regulations in response to METH, we performed strand-specific RNA sequencing (ssRNA-Seq) to identify alterations in mRNA expression and their alternative splicing in the nucleus accumbens of mice following exposure to METH. METH-mediated changes in mRNAs were analyzed and correlated with previously reported changes in non-coding RNAs (miRNAs and lncRNAs) to determine the potential functions of these mRNA changes observed here and how non-coding RNAs are involved. A total of 2171 mRNAs were differentially expressed in response to METH with functions involved in synaptic plasticity, mitochondrial energy metabolism and immune response. 309 and 589 of these mRNAs are potential targets of miRNAs and lncRNAs respectively. In addition, METH treatment decreases mRNA alternative splicing, and there are 818 METH-specific events not observed in saline-treated mice. Our results suggest that METH-mediated addiction could be attributed by changes in miRNAs and lncRNAs and consequently, changes in mRNA alternative splicing and expression. In conclusion, our study reported a methamphetamine-modified nucleus accumbens transcriptome and provided non-coding RNA-mRNA interaction networks possibly involved in METH addiction.

Choline Ameliorates Disease Phenotypes in Human iPSC Models of Rett Syndrome.

Rett syndrome (RTT) is a postnatal neurodevelopmental disorder that primarily affects girls. Mutations in the methyl-CpG-binding protein 2 (MECP2) gene account for approximately 95 % of all RTT cases. To model RTT in vitro, we generated induced pluripotent stem cells (iPSCs) from fibroblasts of two RTT patients with different mutations (MECP2 (R306C) and MECP2 (1155Δ32)) in their MECP2 gene. We found that these iPSCs were capable of differentiating into functional neurons. Compared to control neurons, the RTT iPSC-derived cells had reduced soma size and a decreased amount of synaptic input, evident both as fewer Synapsin 1-positive puncta and a lower frequency of spontaneous excitatory postsynaptic currents. Supplementation of the culture media with choline rescued all of these defects. Choline supplementation may act through changes in the expression of choline acetyltransferase, an important enzyme in cholinergic signaling, and also through alterations in the lipid metabolite profiles of the RTT neurons. Our study elucidates the possible mechanistic pathways for the effect of choline on human RTT cell models, thereby illustrating the potential for using choline as a nutraceutical to treat RTT.

Lentiviral silencing of GSK-3ß in adult dentate gyrus impairs contextual fear memory and synaptic plasticity.

Attempts have been made to use glycogen synthase kinase-3 beta (GSK3ß) inhibitors for prophylactic treatment of neurocognitive conditions. However the use of lithium, a non-specific inhibitor of GSK3ß results in mild cognitive impairment in humans. The effects of global GSK3ß inhibition or knockout on learning and memory in healthy adult mice are also inconclusive. Our study aims to better understand the role of GSK3ß in learning and memory through a more regionally, targeted approach, specifically performing lentiviral-mediated knockdown of GSK3ß within the dentate gyrus (DG). DG-GSK3ß-silenced mice showed impaired contextual fear memory retrieval. However, cue fear memory, spatial memory, locomotor activity and anxiety levels were similar to control. These GSK3ß-silenced mice also showed increased induction and maintenance of DG long-term potentiation (DG-LTP) compared to control animals. Thus, this region-specific, targeted knockdown of GSK3ß in the DG provides better understanding on the role of GSK3ß in learning and memory.

The methyl-CpG-binding domain (MBD) is crucial for MeCP2's dysfunction-induced defects in adult newborn neurons.

Mutations in the human X-linked gene MECP2 are responsible for most Rett syndrome (RTT) cases, predominantly within its methyl-CpG-binding domain (MBD). To examine the role of MBD in the pathogenesis of RTT, we generated two MeCP2 mutant constructs, one with a deletion of MBD (MeCP2-ΔMBD), another mimicking a mutation of threonine 158 within the MBD (MeCP2-T158M) found in RTT patients. MeCP2 knockdown resulted in a decrease in total dendrite length, branching, synapse number, as well as altered spontaneous Ca(2+) oscillations in vitro, which could be reversed by expression of full length human MeCP2 (hMeCP2-FL). However, the expression of hMeCP2-ΔMBD in MeCP2-silenced neurons did not rescue the changes in neuronal morphology and spontaneous Ca(2+) oscillations, while expression of hMeCP2-T158M in these neurons could only rescue the decrease in dendrite length and branch number. In vivo over expression of hMeCP2-FL but not hMeCP2-ΔMBD in adult newborn neurons of the dentate gyrus also rescued the cell autonomous effect caused by MeCP2 deficiency in dendrites length and branching. Our results demonstrate that an intact and functional MBD is crucial for MeCP2 functions in cultured hippocampal neurons and adult newborn neurons.

Rescue of Methyl-CpG Binding Protein 2 Dysfunction-induced Defects in Newborn Neurons by Pentobarbital.

Rett syndrome is a neurodevelopmental disorder that usually arises from mutations or deletions in methyl-CpG binding protein 2 (MeCP2), a transcriptional regulator that affects neuronal development and maturation without causing cell loss. Here, we show that silencing of MeCP2 decreased neurite arborization and synaptogenesis in cultured hippocampal neurons from rat fetal brains. These structural defects were associated with alterations in synaptic transmission and neural network activity. Similar retardation of dendritic growth was also observed in MeCP2-deficient newborn granule cells in the dentate gyrus of adult mouse brains in vivo, demonstrating direct and cell-autonomous effects on individual neurons. These defects, caused by MeCP2 deficiency, were reversed by treatment with the US Food and Drug Administration-approved drug, pentobarbital, in vitro and in vivo, possibly caused by modulation of γ-aminobutyric acid signaling. The results indicate that drugs modulating γ-aminobutyric acid signaling are potential therapeutics for Rett syndrome.