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Barley grass possesses high nutritional value and antioxidant properties. In this study, the phytochemical constituents and antioxidant enzyme activities in six cultivars of barley grass were explored at three developmental stages: tillering, jointing, and booting stages. Total chlorophyll (Chl t) and carotenoid (Car) content, chlorophyll a/b (Chl a/b) ratio, total nitrogen nutrition (TNN), and total soluble protein (TSP) content, and superoxide dismutase (SOD), peroxidase (POD), and polyphenol oxidase (PPO) activities were assayed. The results indicated that the cultivar × development interaction was significant and that developmental stage was the main factor affecting the parameters studied. Cultivars had a negligible effect on these parameters, which varied with the developmental stages. In the tillering stage, Chl t and Car content, TNN, and POD activity achieved their highest value; in the jointing stage, SOD activity peaked; in the booting stage, Chl a/b ratio, TSP content, and PPO activity showed their highest values. TNN showed a negative correlation with TSP. Compared with those in the jointing, Chl t, Car, TSP, TNN content, Chl a/b ratio, and POD and PPO activities increased in the booting and the tillering stages, whereas SOD activity decreased. The differences in phytochemical constituents and antioxidant enzyme activities in barley grass were mainly correlated with the developmental stages. The aim of this study was to demonstrate the influence of developmental stages of barley grass on its phytochemical profile and antioxidant activities. Our results will help understand the mechanism of action of barley grass and provide theoretical support for the therapeutic application of barley grass.

Methyl-CpG binding protein 2 (MeCP2) has crucial roles in transcriptional regulation and microRNA processing (1-4). Mutations in the MECP2 gene are found in 90% of patients with Rett syndrome, a [...]

The pressure–temperature (P‐T) path of blueschist is usually applied to understanding the evolution of the subducted oceanic crust. Garnet plays a key role in calculating the metamorphic conditions, but sometimes it is absent in the blueschists. Nevertheless, the high‐P experimental simulation may serve as a useful tool to constrain the P‐T conditions. In the middle of the Longmu Co‐Shuanghu Suture, North Tibet, blueschist blocks embedded in the marble were discovered, where garnet is abundant in the core but absent in the marble‐contacting margin. These two kinds of blueschist contain similar mineral assemblage (glaucophane, epidote, and phengite) and show comparable basaltic character. Pseudosection modelling was applied to the garnet‐bearing blueschist that calculated the peak metamorphic condition of ca. 1.9 GPa and 530°C. As for the garnet‐absent blueschist, experiments (1.2–2.3 GPa and 500–800°C) were performed on the designed mixture of 93 wt% basalt and 7 wt% calcite. The results show that the total Fe content in the glaucophane and barroisite is positively correlated with the pressure but not with temperature, which could be regarded as a geobarometer. Accordingly, the peak condition was constrained at 2.3 GPa and 500–600°C. Therefore, the equivalent metamorphic conditions of the blueschists indicate that the Palaeo‐Tethys oceanic crust subducted into at least 70 km. Furthermore, both the experiments and the T‐X (CaCO3) pseudosection, constructed based on basaltic lithology, support that the absence of garnet in the blueschist is predominantly caused by the mixing of calcite. In summary, this study provides a valid attempt in exploring metamorphic conditions by experiment simulation, and evaluates the profound influence of the interaction between the basaltic crust and overlying carbonate‐bearing sediments in the subduction zone. [ABSTRACT FROM AUTHOR]

Marmosets are highly social non-human primates that live in families. They exhibit rich vocalization, but the neural basis underlying this complex vocal communication is largely unknown. Here we report the existence of specific neuron populations in marmoset A1 that respond selectively to distinct simple or compound calls made by conspecific marmosets. These neurons were spatially dispersed within A1 but distinct from those responsive to pure tones. Call-selective responses were markedly diminished when individual domains of the call were deleted or the domain sequence was altered, indicating the importance of the global rather than local spectral-temporal properties of the sound. Compound call-selective responses also disappeared when the sequence of the two simple-call components was reversed or their interval was extended beyond 1 s. Light anesthesia largely abolished call-selective responses. Our findings demonstrate extensive inhibitory and facilitatory interactions among call-evoked responses, and provide the basis for further study of circuit mechanisms underlying vocal communication in awake non-human primates. [ABSTRACT FROM AUTHOR]

This paper investigates the methods to detect and classify marmoset vocalizations automatically using a large data set of marmoset vocalizations and deep learning techniques. For vocalization detection, neural networks-based methods, including deep neural network (DNN) and recurrent neural network with long short-term memory units, are designed and compared against a conventional rule-based detection method. For vocalization classification, three different classification algorithms are compared, including a support vector machine (SVM), DNN, and long short-term memory recurrent neural networks (LSTM-RNNs). A 1500-min audio data set containing recordings from four pairs of marmoset twins and manual annotations is employed for experiments. Two test sets are built according to whether the test samples are produced by the marmosets in the training set (test set I) or not (test set II). Experimental results show that the LSTM-RNN-based detection method outperformed others and achieved 0.92% and 1.67% frame error rate on these two test sets. Furthermore, the deep learning models obtained higher classification accuracy than the SVM model, which was 95.60% and 91.67% on the two test sets, respectively. [ABSTRACT FROM AUTHOR]

Intrinsic electric activities of neurons play important roles in establishing and refining neural circuits during development. However, how the underlying ionic currents undergo postembryonic reorganizations remains largely unknown. Using acutely dissociated neurons from larval, pupal, and adultDrosophilabrains, we show drastic re-assemblies and compensatory regulations of voltage-gated (IKv) and Ca2+-activated (IK(Ca)) K+ currents during postembryonic development. Larval and adult neurons displayed prominent fast-inactivating IKv, mediated by theShaker(Sh) channel to a large extent, while in the same neurons IK(Ca)was far smaller in amplitude. In contrast, pupal neurons were characterized by large sustained IKvand prominent IK(Ca), encoded predominantly by theslowpoke(slo) gene. Surprisingly, deletion ofShin theShMnull mutant removed inactivating, transient IKvfrom large portions of neurons at all stages. Interestingly, elimination ofShcurrents was accompanied by upregulation of non-Shtransient IKv. In comparison, theslo1mutation abolished the vast majority of IK(Ca), particularly at the pupal stage. Strikingly, the deficiency of IK(Ca)inslopupae was compensated by the transient component of IKvmediated byShchannels. Thus, IK(Ca)appears to play critical roles in pupal development and its absence induces functional compensations from a specific transient IKvcurrent. While mutants lacking eitherShorslocurrents survived normally,Sh;;slodouble mutants deficient in both failed to survive through pupal metamorphosis. Together, our data highlight significant reorganizations and homeostatic compensations of K+ currents during postembryonic development and uncover previously unrecognized roles forShandsloin this plastic process. [ABSTRACT FROM AUTHOR]

Abstract: We identified a leafy head mutant pla1-5 (plastochron 1-5) from the progeny of japonica rice cultivar Taipei 309 treated with 60Co-γ ray irradiation. The pla1-5 mutant has a dwarf phenotype and small leaves. Compared with its wild type, pla1-5 has more leaves and fewer tillers, and it fails to produce normal panicles at the maturity stage. Genetic analysis showed that the pla1-5 phenotype is controlled by a single recessive nuclear gene. Using the map-based cloning strategy, we narrowed down the location of the target gene to a 58-kb region between simple sequence repeat markers CHR1027 and CHR1030 on the long arm of chromosome 10. The target gene cosegregated with molecular markers CHR1028 and CHR1029. There were five predicted genes in the mapped region. The results from sequencing analysis revealed that there was one base deletion in the first exon of LOC_Os10g26340 encoding cytochrome P450 CYP78A11 in the pla1-5 mutant, which might result in a downstream frame shift and premature termination. These results suggest that the P450 CYP78A11 gene is the candidate gene of PLA1-5. [Copyright &y& Elsevier]

The mechanism underlying the pathogenesis of schizophrenia remains poorly understood. The hyper-dopamine and hypo-NMDA receptor hypotheses have been the most enduring ideas. Recently, emerging evidence implicates alterations of the major inhibitory system, GABAergic neurotransmission in the schizophrenic patients. However, the pathophysiological role of GABAergic system in schizophrenia still remains dubious. In this study, we took advantage of GABA transporter 1 (GAT1) knockout (KO) mouse, a unique animal model with elevated ambient GABA, to study the schizophrenia-related behavioral abnormalities. We found that GAT1 KO mice displayed multiple behavioral abnormalities related to schizophrenic positive, negative and cognitive symptoms. Moreover, GAT1 deficiency did not change the striatal dopamine levels, but significantly enhanced the tonic GABA currents in prefrontal cortex. The GABAA receptor antagonist picrotoxin could effectively ameliorate several behavioral defects of GAT1 KO mice. These results identified a novel function of GAT1, and indicated that the elevated ambient GABA contributed critically to the pathogenesis of schizophrenia. Furthermore, several commonly used antipsychotic drugs were effective in treating the locomotor hyperactivity in GAT1 KO mice, suggesting the utility of GAT1 KO mice as an alternative animal model for studying schizophrenia pathogenesis and developing new antipsychotic drugs. [ABSTRACT FROM AUTHOR]

The molecular mechanisms underlying the involvement of oligodendrocytes in formation of the nodes of Ranvier (NORs) remain poorly understood. Here we show that oligodendrocyte-myelin glycoprotein (OMgp) aggregates specifically at NORs. Nodal location of OMgp does not occur along demyelinated axons of either Shiverer or proteolipid protein (PLP) transgenic mice. Over-expression of OMgp in OLN-93 cells facilitates process outgrowth. In transgenic mice in which expression of OMgp is down-regulated, myelin thickness declines, and lateral oligodendrocyte loops at the node-paranode junction are less compacted and even join together with the opposite loops, which leads to shortened nodal gaps. Notably, each of these structural abnormalities plus modest down-regulation of expression of Na+ channel ± subunit result in reduced conduction velocity in the spinal cords of the mutant mice. Thus, OMgp that is derived from glia has distinct roles in regulating nodal formation and function during CNS myelination. [ABSTRACT FROM PUBLISHER]

Drosophila mutants provide an ideal model to study channel-type specificity of ion channel regulation in situ. In this study, the effects of divalent cations on voltage-gated K + currents were investigated in acutely dissociated central neurons of Drosophila third instar larvae using the whole-cell patch-clamp recording. Our data showed that micromolar Cd 2+ enhanced the peak inactivating current (I A ) without affecting the delayed component (I K ). The same results were obtained in Ca 2+ -free external solution, and from slo 1 mutation, which eliminates transient Ca 2+ -activated K + current. Micromolar Cd 2+ and Zn 2+ , and millimolar Ca 2+ and Mg 2+ all shifted the steady-state inactivation curve of I A without affecting the voltage-dependence of I A activation, whereas millimolar Cd 2+ markedly affected both the activation and steady-state inactivation curves for I A . Divalent cations affected I A with different potency; the sequence was: Zn 2+ > Cd 2+ > Ca 2+ > Mg 2+ . The modulation of I A by Cd 2+ was partially inhibited in Sh M , a null Shaker (one of I A -encoding genes) mutation. Taken together, the channel-type specificity, the asymmetric effects on I A activation and inactivation kinetics, and the diverse potency of divalent cations all strongly support the idea that physiological divalent cations modulate A-type K + channels through specific binding to extracellular sites of the channels. [ABSTRACT FROM AUTHOR]

Barley grass possesses high nutritional value and antioxidant properties. In this study, the phytochemical constituents and antioxidant enzyme activities in six cultivars of barley grass were explored at three developmental stages: tillering, jointing, and booting stages. Total chlorophyll (Chl t) and carotenoid (Car) content, chlorophyll a/b (Chl a/b) ratio, total nitrogen nutrition (TNN), and total soluble protein (TSP) content, and superoxide dismutase (SOD), peroxidase (POD), and polyphenol oxidase (PPO) activities were assayed. The results indicated that the cultivar × development interaction was significant and that developmental stage was the main factor affecting the parameters studied. Cultivars had a negligible effect on these parameters, which varied with the developmental stages. In the tillering stage, Chl t and Car content, TNN, and POD activity achieved their highest value; in the jointing stage, SOD activity peaked; in the booting stage, Chl a/b ratio, TSP content, and PPO activity showed their highest values. TNN showed a negative correlation with TSP. Compared with those in the jointing, Chl t, Car, TSP, TNN content, Chl a/b ratio, and POD and PPO activities increased in the booting and the tillering stages, whereas SOD activity decreased. The differences in phytochemical constituents and antioxidant enzyme activities in barley grass were mainly correlated with the developmental stages. The aim of this study was to demonstrate the influence of developmental stages of barley grass on its phytochemical profile and antioxidant activities. Our results will help understand the mechanism of action of barley grass and provide theoretical support for the therapeutic application of barley grass. [ABSTRACT FROM AUTHOR]

Abstract: GABA transporter-1 (GAT1) plays a key role in GABA reuptake, and deletion of GAT1 leads to a largely increased GABA-induced tonic conductance in the GAT1−/− mice. We hypothesized that homeostatic plasticity of GABAA receptor-mediated inhibition takes place to balance the increased tonic inhibition and maintains stability of the nervous system. In this study, we employed the loss of righting reflex assay and compared the behavioral difference of three animal models, mice with acute, partial, and permanent GAT1 deficiency, to confirm our hypothesis. Our data demonstrated that both acute and partial block of GAT1 increased the sensitivity of mice to GABAergic sedative/hypnotic drugs, whereas permanent GAT1 dysfunction in the GAT1−/− mice decreased the sensitivity to some extent. These results confirmed our presumption about the down-regulation of phasic GABAergic transmission in the GAT1 knockout mice. Moreover, electrophysiological measurements performed on slices from motor cortex suggested that it was the reduced GABA release, but not change of postsynaptic GABA receptors, which led to the down-regulation of phasic inhibition in GAT1−/− mice. [Copyright &y& Elsevier]

Abstract: Enhancing inhibition via gamma-aminobutyric acid type A (GABAA) receptors contributes to anesthetic-induced impairment of long-term potentiation (LTP) of excitatory synaptic transmission, which may account for general anesthesia-associated memory impairment (amnesia). The neuron-specific K+–Cl− cotransporter 2 (KCC2) is necessary for fast synaptic inhibition via maintaining the low intracellular chloride concentration required for the hyperpolarizing actions of GABA via GABAA receptors. To explore a possible role of KCC2-dependent inhibition in anesthetic-induced impairment of LTP, we used field excitatory postsynaptic potentials (fEPSP) recording and immunoblotting to study the effect of propofol on LTP maintenance and KCC2 expression in CA1 region of rat hippocampal slices. We found that propofol (30μM) not only impaired LTP expression but also prevented LTP-accompanied downregulation of KCC2 without affecting the basal transmission of glutamatergic synapses. Moreover, the recurrent inhibition in hippocampal slices was enhanced by propofol. These propofol-induced effects were completely abolished by picrotoxin, a specific GABAA receptor-chloride channel blocker. Thus, enhancement of GABAergic inhibition and suppression of neuronal excitability may account for the sustained expression of KCC2 and the impairment of LTP by propofol. Together, this study supports a novel role for KCC2 in LTP expression and gives hints to a molecular mechanism, by which anesthetics might cause impairment of LTP. [Copyright &y& Elsevier]

Summary Mirror self-recognition is a hallmark of higher intelligence in humans. Most children recognize themselves in the mirror by 2 years of age [ 1 ]. In contrast to human and some great apes, monkeys have consistently failed the standard mark test for mirror self-recognition in all previous studies [ 2–10 ]. Here, we show that rhesus monkeys could acquire mirror-induced self-directed behaviors resembling mirror self-recognition following training with visual-somatosensory association. Monkeys were trained on a monkey chair in front of a mirror to touch a light spot on their faces produced by a laser light that elicited an irritant sensation. After 2–5 weeks of training, monkeys had learned to touch a face area marked by a non-irritant light spot or odorless dye in front of a mirror and by a virtual face mark on the mirroring video image on a video screen. Furthermore, in the home cage, five out of seven trained monkeys showed typical mirror-induced self-directed behaviors, such as touching the mark on the face or ear and then looking at and/or smelling their fingers, as well as spontaneously using the mirror to explore normally unseen body parts. Four control monkeys of a similar age that went through mirror habituation but had no training of visual-somatosensory association did not pass any mark tests and did not exhibit mirror-induced self-directed behaviors. These results shed light on the origin of mirror self-recognition and suggest a new approach to studying its neural mechanism. [ABSTRACT FROM AUTHOR]

Abstract: It has not been reported whether thiamine deficiency (TD) affects hippocampal neurogenesis or not. Here, we explored the influence of TD at early pre-pathological lesion stage on hippocampal neurogenesis and the correlation between affected hippocampal neurogenesis and cognitive dysfunction. We prepared TD mouse model by feeding a thiamine-depleted diet. Learning and memory functions of TD mice were tested with Y-maze. Hippocampal neurogenesis was studied with BrdU, PCNA, Dcx, and NeuN immunohistochemical staining. The results showed significant decline in learning ability and hippocampal neurogenesis simultaneously since 9–days of treatment when the model mice did not exhibit regular pathological lesion, the loss of cholinergic neurons, decrease of NeuN-positive hippocampal cell, and abnormal long-term potentiation of hippocampal CA1 and CA3. Re-administering thiamine reversed the weakened learning ability as well as the impaired hippocampal neurogenesis induced by TD at early pre-pathological lesion stage. The present study demonstrated that hippocampal neurogenesis was vulnerable to TD and the impaired hippocampal neurogenesis is greatly involved in cognitive dysfunction induced by TD at early pre-pathological lesion stage. [Copyright &y& Elsevier]

The common marmoset (Callithrix jacchus) has attracted much attention as a useful model for studying social behaviors [ 1–3 ]. They naturally live in a monogamous family group and exhibit cooperative breeding [ 4 ], in which parents and older siblings help to carry infants less than 2 months old [ 5–7 ]. Marmoset parents also transfer foods to their offspring, a process that may help them learn the food diet [ 8 ]. Furthermore, marmosets show spontaneous altruistic behaviors, such as providing food to non-reciprocating and genetically unrelated individuals [ 9 ]. These social habits indicate that marmosets may be a useful non-human primate model for studying parenting and altruistic behaviors, as well as underlying neural mechanisms. Using a novel rescue paradigm, we found that marmoset parents and older siblings showed strong motivation to rescue trapped young infants but not juvenile marmosets beyond 2 months of age, and infant calls alone could trigger these parents' rescue behaviors. The marmoset parents showed little rescue of each other, but young infants or infant calls could also induce such parents' mutual rescue. Moreover, all these infant- and mate-rescue behaviors depended on currently having young infants in the family group. Functional MRI studies on awake adult marmosets showed that calls from young infants, but not juvenile marmosets, elicited a large-scale activation of specific brain areas including auditory and insular cortices, and such activation was absent in marmosets not living with infants. Thus, such infant-induced modification of neural activity offers a window for examining the neural basis of altruistic behaviors in marmoset monkeys. • We developed a novel rescue paradigm for studying altruistic behaviors in marmosets • Marmoset parents and older siblings show strong motivation to rescue infants • Having infants in the group promotes infant- and mate-rescue behaviors in marmosets • Having infants alters infant-call-elicited brain activation in marmoset parents Using a novel rescue paradigm, Huang et al. find that marmoset monkeys show altruistic behavior by rescuing trapped group members including young infants and mates. All these rescue behaviors depend on currently having young infants in the group. Furthermore, having infants alters infant-call-elicited brain activation in marmoset parents. [ABSTRACT FROM AUTHOR]

The common marmoset ( Callithrix jacchus ) has emerged as a valuable nonhuman primate model in biomedical research with the recent release of high-quality reference genome assemblies. Epileptic marmosets have been independently reported in two Asian primate research centers. Nevertheless, the population genetics within these primate centers and the specific genetic variants associated with epilepsy in marmosets have not yet been elucidated. Here, we characterized the genetic relationships and risk variants for epilepsy in 41 samples from two epileptic marmoset pedigrees using whole-genome sequencing. We identified 14 558 184 single nucleotide polymorphisms (SNPs) from the 41 samples and found higher chimerism levels in blood samples than in fingernail samples. Genetic analysis showed fourth-degree of relatedness among marmosets at the primate centers. In addition, SNP and copy number variation (CNV) analyses suggested that the WW domain-containing oxidoreductase ( WWOX ) and Tyrosine-protein phosphatase nonreceptor type 21 ( PTPN21 ) genes may be associated with epilepsy in marmosets. Notably, KCTD18-like gene deletion was more common in epileptic marmosets than control marmosets. This study provides valuable population genomic resources for marmosets in two Asian primate centers. Genetic analyses identified a reasonable breeding strategy for genetic diversity maintenance in the two centers, while the case-control study revealed potential risk genes/variants associated with epilepsy in marmosets.

The aging of the population and environmental noise have contributed to high rates of presbycusis, also known as age-related hearing loss (ARHL). Because mice have a relatively short life span, murine models have not been suitable for determining the mechanism of presbycusis development and methods of diagnosis. Although the common marmoset, a non-human primate (NHP), is an ideal animal model for studying age-related diseases, its auditory spectrum has not been systematically studied. Auditory brainstem responses (ABRs) from 38 marmosets of different ages demonstrated that auditory function correlated with age. Hearing loss in geriatric common marmosets started at ultra-high frequency (>16 kHz), then extended to lower frequencies. Despite age-related deterioration of ABR threshold and amplitude in marmosets, outer hair cell (OHC) function remained stable at all ages. Spiral ganglion neurons (SGNs), which are the first auditory neurons in the auditory system, were found to degenerate distinctly in aged common marmosets, indicating that neural degeneration caused presbycusis in these animals. Similarly, age-associated ABR deterioration without loss of OHC function was observed in another NHP, rhesus monkeys. Audiometry results from these two species of NHP suggested that NHPs were ideal for studying ARHL and that neural presbycusis at high frequency may be prevalent in primates.

Intrinsic electric activities of neurons play important roles in establishing and refining neural circuits during development. However, how the underlying ionic currents undergo postembryonic reorganizations remains largely unknown. Using acutely dissociated neurons from larval, pupal, and adult Drosophila brains, we show drastic re-assemblies and compensatory regulations of voltage-gated (I Kv ) and Ca 2+ -activated (I K(Ca) ) K +  currents during postembryonic development. Larval and adult neurons displayed prominent fast-inactivating I Kv , mediated by the Shaker (Sh) channel to a large extent, while in the same neurons I K(Ca) was far smaller in amplitude. In contrast, pupal neurons were characterized by large sustained I Kv and prominent I K(Ca) , encoded predominantly by the slowpoke (slo) gene. Surprisingly, deletion of Sh in the Sh M null mutant removed inactivating, transient I Kv from large portions of neurons at all stages. Interestingly, elimination of Sh currents was accompanied by upregulation of non-Sh transient I Kv . In comparison, the slo 1 mutation abolished the vast majority of I K(Ca) , particularly at the pupal stage. Strikingly, the deficiency of I K(Ca) in slo pupae was compensated by the transient component of I Kv mediated by Sh channels. Thus, I K(Ca) appears to play critical roles in pupal development and its absence induces functional compensations from a specific transient I Kv current. While mutants lacking either Sh or slo currents survived normally, Sh;;slo double mutants deficient in both failed to survive through pupal metamorphosis. Together, our data highlight significant reorganizations and homeostatic compensations of K +  currents during postembryonic development and uncover previously unrecognized roles for Sh and slo in this plastic process.

Reduction of glucose metabolism in brain is one of the main features of Alzheimer's disease. Thiamine (vitamin B1)-dependent processes are critical in glucose metabolism and have been found to be impaired in brains from patients with Alzheimer's disease. However, thiamine treatment exerts little beneficial effect in these patients. Here, we tested the effect of benfotiamine, a thiamine derivative with better bioavailability than thiamine, on cognitive impairment and pathology alterations in a mouse model of Alzheimer's disease, the amyloid precursor protein/presenilin-1 transgenic mouse. We show that after a chronic 8 week treatment, benfotiamine dose-dependently enhanced the spatial memory of amyloid precursor protein/presenilin-1 mice in the Morris water maze test. Furthermore, benfotiamine effectively reduced both amyloid plaque numbers and phosphorylated tau levels in cortical areas of the transgenic mice brains. Unexpectedly, these effects were not mimicked by another lipophilic thiamine derivative, fursultiamine, although both benfotiamine and fursultiamine were effective in increasing the levels of free thiamine in the brain. Most notably, benfotiamine, but not fursultiamine, significantly elevated the phosphorylation level of glycogen synthase kinase-3alpha and -3beta, and reduced their enzymatic activities in the amyloid precursor protein/presenilin-1 transgenic brain. Therefore, in the animal Alzheimer's disease model, benfotiamine appears to improve the cognitive function and reduce amyloid deposition via thiamine-independent mechanisms, which are likely to include the suppression of glycogen synthase kinase-3 activities. These results suggest that, unlike many other thiamine-related drugs, benfotiamine may be beneficial for clinical Alzheimer's disease treatment.

The network oscillation and synaptic plasticity are known to be regulated by GABAergic inhibition, but how they are affected by changes in the GABA transporter activity remains unclear. Here we show that in the CA1 region of mouse hippocampus, pharmacological blockade or genetic deletion of GABA transporter-1 (GAT1) specifically impaired long-term potentiation (LTP) induced by theta burst stimulation, but had no effect on LTP induced by high-frequency stimulation or long-term depression induced by low-frequency stimulation. The extent of LTP impairment depended on the precise burst frequency, with significant impairment at 3-7 Hz that correlated with the time course of elevated GABAergic inhibition caused by GAT1 disruption. Furthermore, in vivo electrophysiological recordings showed that GAT1 gene deletion reduced the frequency of hippocampal theta oscillation. Moreover, behavioral studies showed that GAT1 knock-out mice also exhibited impaired hippocampus-dependent learning and memory. Together, these results have highlighted the important link between GABAergic inhibition and hippocampal theta oscillation, both of which are critical for synaptic plasticity and learning behaviors.

Aim: To evaluate the efficacy and tolerability of two different preparations of esomeprazole in healing duodenal ulcers., Methods: A total of 60 patients with active duodenal ulcers were enrolled and randomized to receive esomeprazole enteric-coated capsules (40 mg) or esomeprazole magnesium (40 mg), once daily, for 4 consecutive wk, with ulcer healing being monitored by endoscopy. Safety and tolerability were also assessed., Results: Fifty seven patients completed the whole trial. The ulcer healing rates at the end of wk 2 were 86.7% and 85.2% in the esomeprazole enteric-coated capsules and esomeprazole magnesium groups, respectively (P = 0.8410), and reached 100% at the end of wk 4 in both groups. Symptom relief at the end of wk 2 was 90.8% in the esomeprazole enteric-coated capsules group and 86.7% in the esomeprazole magnesium group (P = 0.5406); at the end of wk 4 symptom relief was 95.2% and 93.2%, respectively (P = 0.5786). Adverse events occurred in 16.7% of the esomeprazole enteric-coated capsules group and 14.8% of the esomeprazole magnesium group (P = 1.0000)., Conclusion: The efficacies of esomeprazole enteric-coated capsules and esomeprazole magnesium in healing duodenal ulcer lesions and relieving gastrointestinal symptoms are equivalent. The tolerability and safety of both drugs were comparable.

Functional glycine receptors (GlyRs) are enriched in the hippocampus, but their role in hippocampal function remains unclear. Since the concentration of ambient glycine is determined by the presence of powerful glycine transporter (GlyT), we blocked the reuptake of glycine in hippocampal slices to examine the role of GlyRs. Antagonists of GlyT type 1 (GlyT1) but not that of GlyT type 2 (GlyT2) induced excitatory postsynaptic potential (EPSP)-spike depression, which was reversed by the specific GlyR antagonist strychnine. Moreover, endogenously elevating the glycine concentration with the GlyT1 antagonists facilitated NMDA receptor-dependent long-term potentiation induction, and elicited a strychnine-sensitive chloride current. In addition, impairment of glial function with fluoroacetate blocked the effect of GlyT1 antagonists on the EPSP-spike curve. Furthermore, pretreatment with sarcosine was effective in controlling pentylenetetrazol-induced seizures. These results indicate an essential role of GlyTs in fine-tuning tonic activation of GlyRs and suggest a potential role of GlyR-dependent EPSP-spike depression in hippocampal network stability.

Menthol is a widely-used cooling and flavoring agent derived from mint leaves. In the peripheral nervous system, menthol regulates sensory transduction by activating TRPM8 channels residing specifically in primary sensory neurons. Although behavioral studies have implicated menthol actions in the brain, no direct central target of menthol has been identified. Here we show that menthol reduces the excitation of rat hippocampal neurons in culture and suppresses the epileptic activity induced by pentylenetetrazole injection and electrical kindling in vivo. We found menthol not only enhanced the currents induced by low concentrations of GABA but also directly activated GABA(A) receptor (GABA(A)R) in hippocampal neurons in culture. Furthermore, in the CA1 region of rat hippocampal slices, menthol enhanced tonic GABAergic inhibition although phasic GABAergic inhibition was unaffected. Finally, the structure-effect relationship of menthol indicated that hydroxyl plays a critical role in menthol enhancement of tonic GABA(A)R. Our results thus reveal a novel cellular mechanism that may underlie the ambivalent perception and psychophysical effects of menthol and underscore the importance of tonic inhibition by GABA(A)Rs in regulating neuronal activity.

GABAergic synaptic inhibition plays a critical role in regulating long-term potentiation (LTP) of glutamatergic synaptic transmission and circuit output. The K(+)-Cl(-) cotransporter 2 (KCC2) is an important factor in determining inhibitory GABAergic synaptic strength besides the contribution of GABA(A) receptor. Although much knowledge has been gained regarding activity-dependent downregulation of KCC2 in many pathological conditions, the potential change and contribution of KCC2 in LTP expression is still unknown. In this study, we found that downregulation of KCC2 was accompanied with the occurrence of LTP but not that of long-term depression in hippocampal CA1 region. Meanwhile, KCC2 level in CA3/DG and adjacent cortex was stable in the process of LTP expression in Schaffer collateral synapses. Blockade of NMDA receptor with APV not only prevented LTP induction also abolished the reduction of KCC2. Furthermore, the inhibition of KCC2 function with furosemide directly induced EPSP-spike (E-S) potentiation, an important component of LTP in hippocampus. The present data suggest a novel mechanism that LTP formation is accompanied by the downregulation of KCC2, which is underlying GABAergic strength and most likely contributes to the E-S potentiation following LTP.

The chronic effects of glycine transporter 1 and 2 inhibitors (sarcosine and ALX-1393, respectively) on miniature inhibitory postsynaptic currents were studied in cultured spinal neurons. We found that sarcosine increased the frequency of overall miniature inhibitory postsynaptic currents without affecting the ratio of glycinergic, mixed and GABAergic miniature inhibitory postsynaptic currents, whereas ALX-1393 changed the ratio by increasing the proportions of GABAergic and mixed miniature inhibitory postsynaptic currents without affecting overall mIPSC frequency. We propose that inhibition of glycine transporter 1 by sarcosine increased overall mIPSC frequency via the activation of presynaptic glycine receptors, while inhibition of glycine transporter 2 by ALX-1393 changed the ratio of glycinergic, mixed and GABAergic miniature inhibitory postsynaptic currents by shifting the balance of inhibitory transmitters in vesicles towards gamma-aminobutyric acid.

Sodium salicylate is one of the nonsteroidal antiinflammatory drugs and is clinically used for antiinflammation and chronic pain relief. In the present study, we investigated the actions of sodium salicylate on gamma-aminobutyric acid type A receptor (GABA(A)) current in cultured rat spinal dorsal horn neurons. Sodium salicylate was found to reduce GABA(A) current in a reversible and concentration-dependent manner, but did not change its ion selectivity. Sodium salicylate was effective only when GABA and sodium salicylate were applied together. Application of sodium salicylate immediately before, but not during, the application of GABA did not result in a significant reduction of GABA(A) current. Our results demonstrate that sodium salicylate reversibly attenuates the GABA(A) response of dorsal horn neurons, suggesting that GABA(A) receptors in the region are pharmacological targets of sodium salicylate.