A theory of synaptic transmission.

Rapid and precise neuronal communication is enabled through a highly synchronous release of signaling molecules neurotransmitters within just milliseconds of the action potential. Yet neurotransmitter release lacks a theoretical framework that is both phenomenologically accurate and mechanistically realistic. Here, we present an analytic theory of the action-potential-triggered neurotransmitter release at the chemical synapse. The theory is demonstrated to be in detailed quantitative agreement with existing data on a wide variety of synapses from electrophysiological recordings in vivo and fluorescence experiments in vitro. Despite up to ten orders of magnitude of variation in the release rates among the synapses, the theory reveals that synaptic transmission obeys a simple, universal scaling law, which we confirm through a collapse of the data from strikingly diverse synapses onto a single master curve. This universality is complemented by the capacity of the theory to readily extract, through a fit to the data, the kinetic and energetic parameters that uniquely identify each synapse. The theory provides a means to detect cooperativity among the SNARE complexes that mediate vesicle fusion and reveals such cooperativity in several existing data sets. The theory is further applied to establish connections between molecular constituents of synapses and synaptic function. The theory allows competing hypotheses of short-term plasticity to be tested and identifies the regimes where particular mechanisms of synaptic facilitation dominate or, conversely, fail to account for the existing data for the paired-pulse ratio. The derived trade-off relation between the transmission rate and fidelity shows how transmission failure can be controlled by changing the microscopic properties of the vesicle pool and SNARE complexes. The established condition for the maximal synaptic efficacy reveals that no fine tuning is needed for certain synapses to maintain near-optimal transmission. We discuss the limitations of the theory and propose possible routes to extend it. These results provide a quantitative basis for the notion that the molecular-level properties of synapses are crucial determinants of the computational and information-processing functions in synaptic transmission.

Neurotransmitter Release of Reprogrammed Cells Using Electrochemical Detection Methods.

The detection of neurotransmitter release from reprogrammed human cell is an important demonstration of their functionality. Electrochemistry has the distinct advantages over alternative methods that it allows for the measuring of the analyte of interest at a high temporal resolution. This is necessary for fast events, such as neurotransmitter release and reuptake, which happen in the order of milliseconds to seconds. The precise description of these kinetic events can lead to insights into the function of cells in health and disease and allows for the exploration of events that might be missed using methods that look at absolute concentration values or methods that have a slower sampling rate. In the present chapter, we describe the use of constant potential amperometry and enzyme-coated multielectrode arrays for the detection of glutamate in vitro. These biosensors have the distinct advantage of "self-referencing," a method providing high selectivity while retaining outstanding temporal resolution. Here, we provide a step-by-step user guide for a commercially available system and its application for in vitro systems such as reprogrammed cells.

Xenopus laevis tadpoles exposed to metamifop: Changes in growth, behavioral endpoints, neurotransmitters, antioxidant system and thyroid development.

Pesticides are a major cause of the reduction in the global amphibian population. In this study, the acute toxicity and chronic effects of metamifop on Xenopus laevis (X. laevis) tadpoles were investigated. The 96 h-LC50 value of metamifop on X. laevis tadpoles was 0.634 mg/L, which indicated that metamifop was highly toxic to tadpoles. In the chronic toxicity study, tadpoles were exposed to 0.063 mg/L of metamifop. After 14, 21 and 35 d of exposure, metamifop significantly inhibited the body weight and neurotransmitter synthesis of tadpoles, caused abnormal behavior and interfered with fat metabolism. According to the results of antioxidant enzymes and malondialdehyde (MDA), tadpoles exposed to 0.063 mg/L metamifop suffered severe lipid oxidative damage. Compared with the control group, the thyroid hormone (TH) levels and related gene expression in tadpoles in the treatment group were affected, reflecting the endocrine interference effect of metamifop. The data of this study can enrich our knowledge of the effects of aryloxyphenoxy propionate pesticides on amphibians and highlight the role of metamifop and other pesticides play in global decline of amphibians.

Direct coordination of pterin to FeII enables neurotransmitter biosynthesis in the pterin-dependent hydroxylases.

The pterin-dependent nonheme iron enzymes hydroxylate aromatic amino acids to perform the biosynthesis of neurotransmitters to maintain proper brain function. These enzymes activate oxygen using a pterin cofactor and an aromatic amino acid substrate bound to the FeII active site to form a highly reactive FeIV = O species that initiates substrate oxidation. In this study, using tryptophan hydroxylase, we have kinetically generated a pre-FeIV = O intermediate and characterized its structure as a FeII-peroxy-pterin species using absorption, Mössbauer, resonance Raman, and nuclear resonance vibrational spectroscopies. From parallel characterization of the pterin cofactor and tryptophan substrate-bound ternary FeII active site before the O2 reaction (including magnetic circular dichroism spectroscopy), these studies both experimentally define the mechanism of FeIV = O formation and demonstrate that the carbonyl functional group on the pterin is directly coordinated to the FeII site in both the ternary complex and the peroxo intermediate. Reaction coordinate calculations predict a 14 kcal/mol reduction in the oxygen activation barrier due to the direct binding of the pterin carbonyl to the FeII site, as this interaction provides an orbital pathway for efficient electron transfer from the pterin cofactor to the iron center. This direct coordination of the pterin cofactor enables the biological function of the pterin-dependent hydroxylases and demonstrates a unified mechanism for oxygen activation by the cofactor-dependent nonheme iron enzymes.

Alterations in neurotransmitter levels and transcription factor expression following intranasal buprenorphine administration.

Buprenorphine is an opioid drug used in the management of pain and the treatment opioid addiction. Like other opioids, it is believed that it achieves these effects by altering functional neurotransmitter pathways and the expression of important transcription factors; cyclic AMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) in the brain. However, there is a lack of scientific evidence to support these theories. This study investigated the pharmacodynamic effects of BUP administration by assessing neurotransmitter and molecular changes in the healthy rodent brain. Sprague-Dawley rats (150-200 g) were intranasally administered buprenorphine (0.3 mg/mL) and sacrificed at different time points: 0.25, 0.5, 1, 2, 4, 6, 8 and 24 h post drug administration. LC-MS was used to quantify BUP and neurotransmitters (GABA, GLUT, DA, NE and 5-HT) in the brain, while CREB and BDNF gene expression was determined using qPCR. Results showed that BUP reached a Cmax of 1.21 ± 0.0523 ng/mL after 2 h, with all neurotransmitters showing an increase in their concentration over time, with GABA, GLUT and NE reaching their maximum concentration after 8 h. DA and 5-HT reached their maximum concentrations at 1 h and 24 h, respectively post drug administration. Treatment with BUP resulted in significant upregulation in BDNF expression throughout the treatment period while CREB showed patterns of significant upregulation at 2 and 8 h, and downregulation at 1 and 6 h. This study contributes to the understanding of the pharmacodynamic effects of BUP in opioid addiction by proving that the drug significantly influences NT pathways that are implicated in opioid addiction.

[Importance of choline in cognitive function]. / Importancia de la colina en la función cognitiva.

INTRODUCTION: Choline is a critical nutrient for cognitive development, metabolism and liver function, and regulation of homocysteine metabolism. It is necessary for the synthesis of the neurotransmitter acetylcholine, the synthesis of betaine and that of phosphatidylcholine. In the perinatal stage, the contribution of choline is essential to guarantee optimal cognitive development and prevent neural tube defects. In adults and the elderly, choline intake has been associated with better performance in some cognitive functions and a lower incidence of dementia. Despite their important role in health, most groups of the population do not reach their adequate intake of choline, and even some groups, such as pregnant women or childbearing women, have a higher risk of having suboptimal intakes. The main dietary sources of choline are eggs, dairy and meats, so reducing or limiting the consumption of these foods negatively impacts on the intake of this nutrient. Given the need to improve the intake of this vitamin, it is necessary to increase the knowledge that the population has about this nutrient, raising awareness about the importance of choline for health, and its main food sources.

INTRODUCCIÓN: La colina es un nutriente crítico para el desarrollo cognitivo, el metabolismo y la función hepática y la regulación del metabolismo de la homocisteína. Es necesaria para la síntesis del neurotransmisor acetilcolina, la síntesis de betaína y la de fosfatidilcolina. En la etapa perinatal el aporte de colina es fundamental para garantizar el desarrollo cognitivo y prevenir defectos del tubo neural. En adultos mayores y ancianos la ingesta de colina se ha asociado a mejor rendimiento en algunas funciones cognitivas y menor incidencia de demencia. A pesar de su importante papel en la salud, la mayoría de los colectivos no alcanza sus ingestas adecuadas (IA) de colina, aunque algunos colectivos, como gestantes o mujeres en edad fértil, tienen un mayor riesgo de tener ingestas subóptimas. Las principales fuentes dietéticas de esta vitamina son los huevos, lácteos y carnes, y disminuir o limitar el consumo de estos alimentos impacta negativamente en la ingesta de este nutriente. Dada la necesidad de mejorar la ingesta de esta vitamina, es necesario mejorar el conocimiento que tiene la población sobre este nutriente, concienciándola sobre la importancia de la colina para la salud y sus principales fuentes alimentarias.

Somatostatin expressing GABAergic interneurons in the medial entorhinal cortex preferentially inhibit layerIII-V pyramidal cells.

GABA released from heterogeneous types of interneurons acts in a complex spatio-temporal manner on postsynaptic targets in the networks. In addition to GABA, a large fraction of GABAergic cells also express neuromodulator peptides. Somatostatin (SOM) containing interneurons, in particular, have been recognized as key players in several brain circuits, however, the action of SOM and its downstream network effects remain largely unknown. Here, we used optogenetics, electrophysiologic, anatomical and behavioral experiments to reveal that the dendrite-targeting, SOM+ GABAergic interneurons demonstrate a unique layer-specific action in the medial entorhinal cortex (MEC) both in terms of GABAergic and SOM-related properties. We show that GABAergic and somatostatinergic neurotransmission originating from SOM+ local interneurons preferentially inhibit layerIII-V pyramidal cells, known to be involved in memory formation. We propose that this dendritic GABA-SOM dual inhibitory network motif within the MEC serves to selectively modulate working-memory formation without affecting the retrieval of already learned spatial navigation tasks.

Dialog between skin and its microbiota: Emergence of "Cutaneous Bacterial Endocrinology".

Microbial endocrinology is studying the response of microorganisms to hormones and neurohormones and the microbiota production of hormones-like molecules. Until now, it was mainly applied to the gut and revealed that the intestinal microbiota should be considered as a real organ in constant and bilateral interactions with the whole human body. The skin harbours the second most abundant microbiome and contains an abundance of nerve terminals and capillaries, which in addition to keratinocytes, fibroblasts, melanocytes, dendritic cells and endothelial cells, release a huge diversity of hormones and neurohormones. In the present review, we will examine recent experimental data showing that, in skin, molecules such as substance P, calcitonin gene-related peptide, natriuretic peptides and catecholamines can directly affect the physiology and virulence of common skin-associated bacteria. Conversely, bacteria are able to synthesize and release compounds including histamine, glutamate and γ-aminobutyric acid or peptides showing partial homology with neurohormones such as α-melanocyte-stimulating hormone (αMSH). The more surprising is that some viruses can also encode neurohormones mimicking proteins. Taken together, these elements demonstrate that there is also a cutaneous microbial endocrinology and this emerging concept will certainly have important consequences in dermatology.

Study of BDE-47 induced Parkinson's disease-like metabolic changes in C57BL/6 mice by integrated metabolomic, lipidomic and proteomic analysis.

As the predominant congener of polybrominated diphenyl ethers (PBDEs) detected in human serum, 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) has been reported to induce neurotoxicity. However, the possible linkage between BDE-47 and typical neurodegenerative diseases such as Parkinson's disease (PD) is still unclear. Here we carried out omics studies using liquid chromatography-orbitrap mass spectrometry (LC-orbitrap MS) to depict the BDE-47 induced metabolic changes in C57BJ/L mice to explore the possible contribution of BDE-47 exposure to PD pathology. BDE-47 dissolved in corn oil was orally administered to mice for 30 consecutive days. Results of metabolomics and lipidomics studies of PD-related brain regions revealed significant metabolite changes in pathways involved in oxidative stress and neurotransmitter production. Moreover, isobaric tags for relative and absolute quantitation (iTRAQ) proteomics study of the striatum, which is the part of brain that is most intensively studied in PD pathogenesis, revealed that BDE-47 could induce neurotransmitter system disturbance, abnormal phosphorylation, mitochondrial dysfunction and oxidative stress. Overall, this study depicts the possible contribution of BDE-47 exposure to PD pathology and highlights the powerfulness of omics platforms to deepen the mechanistic understanding of environmental pollutant-caused toxicity.

Increasing carbohydrate availability in the hindgut promotes hypothalamic neurotransmitter synthesis: aromatic amino acids linking the microbiota-brain axis.

The gut microbiota is increasingly recognized to modulate brain function by recent studies demonstrating the central effects of various gut microbial manipulation strategies. Our previous study demonstrated that antibiotic-induced alterations of hindgut microbiota are associated with changes in aromatic amino acid (AAA) metabolism and hypothalamic neurochemistry, while the underlying mechanistic insight is limited. Given that the microbial AAA metabolism can be affected by luminal carbohydrate availability, here we hypothesize that increasing hindgut carbohydrate availability affects the expression of neurotransmitters in the porcine hypothalamus. A hindgut microbiota-targeted strategy was adopted by increasing hindgut carbohydrate availability in a cecal-cannulated piglet model. Mechanistic involvement of AAAs along the gut microbiota-brain axis was further investigated in mice and neuronal cells. Increasing carbohydrate availability by cecal starch infusion led to a decrease in hindgut AAA metabolism, and an increase in systemic AAA availability, central AAA-derived neurotransmitters (5-HT, dopamine), and neurotrophin BDNF in piglets, indicating that hindgut microbiota affect hypothalamic neurochemistry in an AAA-dependent manner. Single AAA i.p. injection in mice revealed that an increase in circulating tryptophan and tyrosine elevated their concentrations in brain and finally promoted the expressions of 5-HT, dopamine, and BDNF in a time-dependent manner. Neuronal cells treated with single AAAs in vitro further demonstrated that tryptophan and tyrosine enhanced 5-HT and dopamine synthesis, respectively, and promoted BDNF expression partly through the 5-HT1A/DRD1-CREB pathway. Our study reveals that increasing hindgut carbohydrate availability promotes hypothalamic neurotransmitter synthesis and that AAAs act as potential mediators between hindgut microbiota and brain neurochemistry.

Protein carbonylation in dopaminergic cells exposed to rotenone.

Rotenone is an environmental neurotoxin that induces degeneration of dopaminergic neurons and the most common features of Parkinson's disease in animal models. It acts as a mitochondrial complex I inhibitor that impairs cellular respiration, with consequent increase of reactive oxygen species and oxidative stress. This study evaluates the rotenone-induced oxidative damage in PC12 cells, focusing particularly on protein oxidation. The identification of specific carbonylated proteins highlighted putative alterations of important cellular processes possibly associated with Parkinson's disease. Carbonylation of ATP synthase and of enzymes acting in pyruvate and glucose metabolism suggested a failure of mechanisms ensuring cellular energy supply. Concomitant oxidation of cytoskeletal proteins and of enzymes involved in the synthesis of neuroactive molecules indicated alterations of the neurotransmission system. Carbonylation of chaperon proteins as well as of proteins acting in the autophagy-lysosome pathway and the ubiquitin-proteasome system suggested the possible formation of cytosolic unfolded protein inclusions as result of defective processes assisting recovery/degradation of damaged molecules. In conclusion, this study originally evidences specific protein targets of rotenone-induced oxidative damage, suggesting some possible molecular mechanisms involved in rotenone toxicity.

Efficacy and mechanism of acupuncture for ischemic poststroke depression: Study protocol for a multicenter single-blinded randomized sham-controlled trial.

INTRODUCTION: Poststroke depression is a serious and common complication of stroke, especially the ischemic poststroke depression. Antidepressants are used in poststroke depression, and acupuncture may be an alternative approach. However, the efficacy and mechanism of acupuncture for poststroke depression has not been confirmed. METHODS/DESIGN: This is a multicenter, central-randomized, single-blind, sham-controlled clinical trial. We will allocate 208 subjects aged between 40 and 80 years old, diagnosed with initial poststroke depression (PSD) within 6 months to 2 groups randomly in a ratio of 1:1. Patients in the experimental group will be treated with traditional acupuncture and placebo pills, whereas the others in the control group will be treated with sham-acupoints acupuncture and antidepressant (fluoxetine hydrochloride tablets). All will be given acupuncture and/or medication treatment for 12 weeks, and then received 12-week follow-up. Patients will be evaluated with the 17-item Hamilton Depression Scale and Se1f-rating Depression Scale for depression state, National Institute of Health Stroke Scale for neurological deficit, Modified Barthel Index for activities of daily living, Treatment Emergent Symptom Scale for side effects of treatments, diagnosis and evaluation criteria of traditional Chinese medicine for stroke (try out) for curative effects of stroke, and clinical global impression for synthesize effect before and the 2nd, 4th, 8th, and 12th week of treatment, 24th week of follow-up. Study on mechanisms of acupuncture will be revealed through the diversity of brain metabolites (choline-containing compounds [Cho], N-acetylaspartate [NAA], myoinositol, glutamine and glutamate complex, creatine [Cr], Cho/Cr, Cho/NAA, Cr/NAA) in bilateral dorsolateral prefrontal cortex and anterior cingulate cortex monitored by proton magnetic resonance spectroscopy, and serum monoamine neurotransmitters (5-hydroxytryptamine, norepinephrine, dopamine) and cytokines (brain-derived neurotrophic factor [BDNF], interleukin [IL]-4, IL-6, IL-10, IL-18, IL-1ß, tumor necrosis factor alpha) before and the 12th week of treatment. Baseline characteristics of patients will be summarized by groups and compared with chi-square for categorical variables, and 2-sample t tests or Wilcoxon rank-sum test for the continuous variables. Primary and secondary outcomes according to the measurement times are applicable to univariate repetitive measurement deviation analysis or 2-sample t tests, or Wilcoxon rank-sum test. CONCLUSION: The present research is designed to investigate efficacy and mechanism of traditional acupuncture therapy on ischemic PSD, also to explore the correlation between cerebra metabolic and serologic factors, and ischemic PSD. With this research, we are looking forward to find out an appropriate alternative nondrug therapy for PSD people to alleviate the adverse effects and drug dependence caused by antidepressants.

Altered expression of genes involved in brain energy metabolism as adaptive responses in rats exposed to chronic variable stress; changes in cortical level of glucogenic and neuroactive amino acids.

Brain metabolism is closely associated with neuronal activity and enables the accurate synthesis and function of neurotransmitters. Although previous studies have demonstrated that chronic stress is associated with the overproduction of reactive oxygen species (ROS), which leads to oxidative stress and the disruption of glucose metabolism, the molecular mechanisms and cerebral gluconeogenesis in depression have not yet been completely elucidated. In order to examine this subject, the present study evaluated changes in the expression of selected genes involved in the glycolytic pathway and the levels of glucogenic and neuroactive amino acids in the brain of rats exposed to chronic variable stress. Male Wistar rats (50­55 days old, weighing 200­250 g) were divided into two groups: control and stressed, and the rats in the stressed group were exposed to stress conditions for 40 days. Depressive­like states were observed and recorded by measuring the body weight and forced swim test (FST). The mRNA levels of Slc2a3 (coding GLUT3) and Tfam (activator of mitochondrial transcription and a participant in mitochondrial genome replication) were markedly increased, while a decrease in the expression of Ldhb and GAPDH was also observed. These modifications were associated with the redirection of glucose metabolism to appropriate defensive pathways under chronic stress conditions, and an increased ability to maintain mitochondrial function as potential adaptive responses. A marked reduction of glucogenic and neuroactive amino acids levels indicate the support of energy metabolism by stimulation of the gluconeogenesis pathway. The findings of the present study provide a novel insight into the molecular and biochemical events that impact the development of depression under chronic stress conditions, and they may identify novel targets for therapeutic intervention.

The dystrophin isoform Dp71eΔ71 is involved in neurite outgrowth and neuronal differentiation of PC12 cells.

The Dp71 protein is the most abundant dystrophin in the central nervous system (CNS). Several dystrophin Dp71 isoforms have been described and are classified into three groups, each with a different C-terminal end. However, the functions of Dp71 isoforms remain unknown. In the present study, we analysed the effect of Dp71eΔ71 overexpression on neuronal differentiation of PC12 Tet-On cells. Overexpression of dystrophin Dp71eΔ71 stimulates neuronal differentiation, increasing the percentage of cells with neurites and neurite length. According to 2-DE analysis, Dp71eΔ71 overexpression modified the protein expression profile of rat pheochromocytoma PC12 Tet-On cells that had been treated with neuronal growth factor (NGF) for nine days. Interestingly, all differentially expressed proteins were up-regulated compared to the control. The proteomic analysis showed that Dp71eΔ71 increases the expression of proteins with important roles in the differentiation process, such as HspB1, S100A6, and K8 proteins involved in the cytoskeletal structure and HCNP protein involved in neurotransmitter synthesis. The expression of neuronal marker TH was also up-regulated. Mass spectrometry data are available via ProteomeXchange with identifier PXD009114. SIGNIFICANCE: This study is the first to explore the role of the specific isoform Dp71eΔ71. The results obtained here support the hypothesis that the dystrophin Dp71eΔ71 isoform has an important role in the neurite outgrowth by regulating the levels of proteins involved in the cytoskeletal structure, such as HspB1, S100A6, and K8, and in neurotransmitter synthesis, such as HCNP and TH, biological processes required to stimulate neuronal differentiation.

Metabolome-wide association study of anti-epileptic drug treatment during pregnancy.

Pregnant women with epilepsy (PWWE) require continuous anti-epileptic drug (AED) treatment to avoid risk to themselves and fetal risks secondary to maternal seizures, resulting in prolonged AED exposure to the developing embryo and fetus. The objectives of this study were to determine whether high-resolution metabolomics is able to link the metabolite profile of PWWE receiving lamotrigine or levetiracetam for seizure control to associated pharmacodynamic (PD) biological responses. Untargeted metabolomic analysis of plasma obtained from 82 PWWE was completed using high-resolution mass spectrometry. Biological alterations due to lamotrigine or levetiracetam monotherapy were determined by a metabolome-wide association study that compared patients taking either drug to those who did not require AED treatment. Metabolic changes associated with AED use were then evaluated by testing for drug-dose associated metabolic variations and pathway enrichment. AED therapy resulted in drug-associated metabolic profiles recognizable within maternal plasma. Both the parent compounds and major metabolites were detected, and each AED was correlated with other metabolic features and pathways. Changes in metabolites and metabolic pathways important to maternal health and linked to fetal neurodevelopment were detected for both drugs, including changes in one­carbon metabolism, neurotransmitter biosynthesis and steroid metabolism. In addition, decreased levels of 5-methyltetrahydrofolate and tetrahydrofolate were detected in women taking lamotrigine, which is consistent with recent findings showing increased risk of autism spectrum disorder traits in PWWE using AED. These results represent a first step in development of pharmacometabolomic framework with potential to detect adverse AED-related metabolic changes during pregnancy.

Molecular characterization of putative neuropeptide, amine, diffusible gas and small molecule transmitter biosynthetic enzymes in the eyestalk ganglia of the American lobster, Homarus americanus.

The American lobster, Homarus americanus, is a model for investigating the neuromodulatory control of physiology and behavior. Prior studies have shown that multiple classes of chemicals serve as locally released/circulating neuromodulators/neurotransmitters in this species. Interestingly, while many neuroactive compounds are known from Homarus, little work has focused on identifying/characterizing the enzymes responsible for their biosynthesis, despite the fact that these enzymes are key components for regulating neuromodulation/neurotransmission. Here, an eyestalk ganglia-specific transcriptome was mined for transcripts encoding enzymes involved in neuropeptide, amine, diffusible gas and small molecule transmitter biosynthesis. Using known Drosophila melanogaster proteins as templates, transcripts encoding putative Homarus homologs of peptide precursor processing (signal peptide peptidase, prohormone processing protease and carboxypeptidase) and immature peptide modifying (glutaminyl cyclase, tyrosylprotein sulfotransferase, protein disulfide isomerase, peptidylglycine-α-hydroxylating monooxygenase and peptidyl-α-hydroxyglycine-α-amidating lyase) enzymes were identified in the eyestalk assembly. Similarly, transcripts encoding full complements of the enzymes responsible for dopamine [tryptophan-phenylalanine hydroxylase (TPH), tyrosine hydroxylase and DOPA decarboxylase (DDC)], octopamine (TPH, tyrosine decarboxylase and tyramine ß-hydroxylase), serotonin (TPH or tryptophan hydroxylase and DDC) and histamine (histidine decarboxylase) biosynthesis were identified from the eyestalk ganglia, as were those responsible for the generation of the gases nitric oxide (nitric oxide synthase) and carbon monoxide (heme oxygenase), and the small molecule transmitters acetylcholine (choline acetyltransferase), glutamate (glutaminase) and GABA (glutamic acid decarboxylase). The presence and identity of the transcriptome-derived transcripts were confirmed using RT-PCR. The data presented here provide a foundation for future gene-based studies of neuromodulatory control at the level of neurotransmitter/modulator biosynthesis in Homarus.

Tannins from Terminalia chebula fruits attenuates GABA antagonist-induced anxiety-like behaviour via modulation of neurotransmitters.

OBJECTIVES: This article investigates the anxiolytic activity of Terminalia chebula tannin-rich extract against picrotoxin (PTX; GABA antagonist)-induced anxiety in mice model. METHODS: Anxiolytic activity was studied by elevated plus maze (EPM), open field test (OFT), light/dark box test (LDT) and Vogel's conflict test (VCT). Electroencephalogram (EEG) was performed to know the changes in brain activity instigated by GABA antagonist. 5-hydroxytryptamine (5-HT), dopamine and norepinephrine levels in brain tissues were estimated by HPLC. The mRNA (CREB, BDNF, GABA, and 5-HT1A ) and protein expression (CREB, p-CREB, BDNF, ERK ½, p-ERK ½, GABAA Rα1, 5-HT1A and GAPDH) levels in brain tissue were determined by RT-PCR and Western blot analysis, respectively. KEY FINDINGS: Terminalia chebula tannin-rich extract (TCHE) supplementation increased locomotion in mice towards open arm (EPM), time spent in illuminated area (LDT), rearing frequency (OFT) and number of shocks (VCT) compared to PTX (P < 0.05). Furthermore, TCHE down-regulated serum cortisol levels and showed increased levels of 5-HT, DA and NE. Gene expressions such as BDNF, CREB, GABAA and 5-HT1A were up-regulated by TCHE treatment compared to PTX. CONCLUSIONS: Terminalia chebula tannin-rich extract showed significant anxiolytic activity against picrotoxin and could be used as natural therapy in neurodegenerative disorders.

Possible mechanism of Vitis vinifera L. flavones on neurotransmitters, synaptic transmission and related learning and memory in Alzheimer model rats.

BACKGROUND: This study explored the possible mechanism of flavones from Vitis vinifera L. (VTF) on neurotransmitters, synaptic transmission and related learning and memory in rats with Alzheimer disease (AD). METHODS: The researchers injected amyloid-ß(25-35) into the hippocampus to establish AD model rats. The Sprague-Dawley (SD) rats were divided into a control group, a donepezil group, an AD model group, a VTF low-dose group, a VTF medium-dose group and a VTF high-dose group. The researchers detected the activity of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) according to kit instructions. The protein expression of brain-derived neurotrophic factor (BDNF), synaptotagmin-1 (SYT1) and cyclic adenosine monophosphate response element binding protein (CREB) in the rats' hippocampi was detected by immunohistochemistry and Western blot, and the gene expression of cAMP-regulated enhancer (CRE) was detected by real-time quantitative polymerase chain reaction (PCR). RESULTS: VTF may enhance the protein expression of p-CREB, BDNF and SYT1 in rat hippocampi, depending on dose. The messenger RNA (mRNA) level of CREB was significantly higher in the VTF high-dose group than in the model group, which was consistent with the results of Western blotting. VTF may reduce the activity of AChE and increase that of ChAT in rat hippocampi. Finally, VTF effectively improved the learning and memory abilities of AD rats. CONCLUSIONS: VTF can promote synaptic plasticity and indirectly affect the expression of cholinergic neurotransmitters, which may be one mechanism of VTF protection in AD rats.

Neurosteroids: non-genomic pathways in neuroplasticity and involvement in neurological diseases.

Neurosteroids are neuroactive brain-born steroids. They can act through non-genomic and/or through genomic pathways. Genomic pathways are largely described for steroid hormones: the binding to nuclear receptors leads to transcription regulation. Pregnenolone, Dehydroepiandrosterone, their respective sulfate esters and Allopregnanolone have no corresponding nuclear receptor identified so far whereas some of their non-genomic targets have been identified. Neuroplasticity is the capacity that neuronal networks have to change their structure and function in response to biological and/or environmental signals; it is regulated by several mechanisms, including those that involve neurosteroids. In this review, after a description of their biosynthesis, the effects of Pregnenolone, Dehydroepiandrosterone, their respective sulfate esters and Allopregnanolone on their targets will be exposed. We then shall highlight that neurosteroids, by acting on these targets, can regulate neurogenesis, structural and functional plasticity. Finally, we will discuss the therapeutic potential of neurosteroids in the pathophysiology of neurological diseases in which alterations of neuroplasticity are associated with changes in neurosteroid levels.

Anxiolytic Therapy: A Paradigm of Successful Mitochondrial Pharmacology.

The complex biochemistry and dynamic structure of mitochondria have prevented them from being prominent pharmacological targets. New mechanistic understanding of cholesterol transport and associated neurosteroidogenesis is providing evidence on therapeutic outcomes in mental disorders that is achievable via mitochondrial pharmacology. This warrants general attention on mitochondrial pharmacology to inform therapies.