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Proceedings of the National Academy of... Dec 2015Protein Numb, first identified as a cell-fate determinant in Drosophila, has been shown to promote the development of neurites in mammals and to be cotransported with...
Protein Numb, first identified as a cell-fate determinant in Drosophila, has been shown to promote the development of neurites in mammals and to be cotransported with endocytic receptors in clathrin-coated vesicles in vitro. Nevertheless, its function in mature neurons has not yet been elucidated. Here we show that cerebellar Purkinje cells (PCs) express high levels of Numb during adulthood and that conditional deletion of Numb in PCs is sufficient to impair motor coordination despite maintenance of a normal cerebellar cyto-architecture. Numb proved to be critical for internalization and recycling of metabotropic glutamate 1 receptor (mGlu1) in PCs. A significant decrease of mGlu1 and an inhibition of long-term depression at the parallel fiber-PC synapse were observed in conditional Numb knockout mice. Indeed, the trafficking of mGlu1 induced by agonists was inhibited significantly in these mutants, but the expression of ionotropic glutamate receptor subunits and of mGlu1-associated proteins was not affected by the loss of Numb. Moreover, transient and persistent forms of mGlu1 plasticity were robustly induced in mutant PCs, suggesting that they do not require mGlu1 trafficking. Together, our data demonstrate that Numb is a regulator for constitutive expression and dynamic transport of mGlu1.
Topics: Animals; Cerebellum; Long-Term Potentiation; Long-Term Synaptic Depression; Membrane Potentials; Membrane Proteins; Methoxyhydroxyphenylglycol; Mice, Knockout; Morphogenesis; Motor Activity; Nerve Tissue Proteins; Patch-Clamp Techniques; Purkinje Cells; Receptors, Metabotropic Glutamate; Synapses
PubMed: 26621723
DOI: 10.1073/pnas.1512915112 -
Serum Metabolic Profiling in a Mouse Model of Adriamycin-Induced Focal Segmental Glomerulosclerosis.Chinese Medical Journal Nov 2018
Topics: Animals; Body Weight; Computational Biology; Disease Models, Animal; Doxorubicin; Fatty Acids, Monounsaturated; Glomerulosclerosis, Focal Segmental; Male; Methoxyhydroxyphenylglycol; Mice; Mice, Inbred BALB C; Pyridoxine; Valine; Vanillic Acid
PubMed: 30425202
DOI: 10.4103/0366-6999.245266 -
Neuron May 2015Deregulation of synaptic plasticity may contribute to the pathogenesis of developmental cognitive disorders. In particular, exaggerated mGluR-dependent LTD is featured...
Deregulation of synaptic plasticity may contribute to the pathogenesis of developmental cognitive disorders. In particular, exaggerated mGluR-dependent LTD is featured in fragile X syndrome, but the mechanisms that regulate mGluR-LTD remain incompletely understood. We report that conditional knockout of Cdh1, the key regulatory subunit of the ubiquitin ligase Cdh1-anaphase-promoting complex (Cdh1-APC), profoundly impairs mGluR-LTD in the hippocampus. Mechanistically, we find that Cdh1-APC operates in the cytoplasm to drive mGluR-LTD. We also identify the fragile X syndrome protein FMRP as a substrate of Cdh1-APC. Endogenous Cdh1-APC forms a complex with endogenous FMRP, and knockout of Cdh1 impairs mGluR-induced ubiquitination and degradation of FMRP in the hippocampus. Knockout of FMRP suppresses, and expression of an FMRP mutant protein that fails to interact with Cdh1 phenocopies, the Cdh1 knockout phenotype of impaired mGluR-LTD. These findings define Cdh1-APC and FMRP as components of a novel ubiquitin signaling pathway that regulates mGluR-LTD in the brain.
Topics: Animals; Animals, Newborn; Anisomycin; Cdh1 Proteins; Female; Fragile X Mental Retardation Protein; HEK293 Cells; Hippocampus; Humans; In Vitro Techniques; Long-Term Potentiation; Male; Methoxyhydroxyphenylglycol; Mice, Transgenic; Protein Synthesis Inhibitors; Receptors, Metabotropic Glutamate; Signal Transduction; Subcellular Fractions; Synapses; Ubiquitin
PubMed: 25913861
DOI: 10.1016/j.neuron.2015.03.049 -
PloS One 2014Stimulation of type I metabotropic glutamate receptors (mGluR1/5) in several neuronal types induces slow excitatory responses through activation of transient receptor...
Stimulation of type I metabotropic glutamate receptors (mGluR1/5) in several neuronal types induces slow excitatory responses through activation of transient receptor potential canonical (TRPC) channels. GABAergic cerebellar molecular layer interneurons (MLIs) modulate firing patterns of Purkinje cells (PCs), which play a key role in cerebellar information processing. MLIs express mGluR1, and activation of mGluR1 induces an inward current, but its precise intracellular signaling pathways are unknown. We found that mGluR1 activation facilitated spontaneous firing of mouse cerebellar MLIs through an inward current mediated by TRPC1 channels. This mGluR1-mediated inward current depends on both G protein-dependent and -independent pathways. The nonselective protein tyrosine kinase inhibitors genistein and AG490 as well as the selective extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitors PD98059 and SL327 suppressed the mGluR1-mediated current responses. Following G protein blockade, the residual mGluR1-mediated inward current was significantly reduced by the selective Src tyrosine kinase inhibitor PP2. In contrast to cerebellar PCs, GABAB receptor activation in MLIs did not alter the mGluR1-mediated inward current, suggesting that there is no cross-talk between mGluR1 and GABAB receptors in MLIs. Thus, activation of mGluR1 facilitates firing of MLIs through the TRPC1-mediated inward current, which depends on not only G protein-dependent but also Src-ERK1/2-dependent signaling pathways, and consequently depresses the excitability of cerebellar PCs.
Topics: Action Potentials; Animals; Cerebellum; Excitatory Postsynaptic Potentials; Extracellular Signal-Regulated MAP Kinases; GABAergic Neurons; GTP-Binding Proteins; Interneurons; Ion Channel Gating; Methoxyhydroxyphenylglycol; Mice, Inbred C57BL; Protein Kinase Inhibitors; Receptors, GABA; Receptors, Metabotropic Glutamate; Signal Transduction; TRPC Cation Channels; Type C Phospholipases; src-Family Kinases
PubMed: 25181481
DOI: 10.1371/journal.pone.0106316 -
BMC Complementary and Alternative... Dec 2014In this study, we investigate the effects of valerian root extracts (VE) on physical and psychological stress responses by utilizing a communication box.
Valeriana officinalis root extract suppresses physical stress by electric shock and psychological stress by nociceptive stimulation-evoked responses by decreasing the ratio of monoamine neurotransmitters to their metabolites.
BACKGROUND
In this study, we investigate the effects of valerian root extracts (VE) on physical and psychological stress responses by utilizing a communication box.
METHODS
Eight-week-old ICR mice received oral administration of VE (100 mg/kg/0.5 ml) or equal volume of distilled water in every day for 3 weeks prior to being subjected to physical or psychological stress for 3 days, which are induced by communication box developed for physical electric shock and psychological stress by nociceptive stimulation-evoked responses. The stress condition was assessed by forced swimming test and serum corticosterone levels. In addition, norepinephrine (NE), serotonin (5-HT), and their metabolites such as 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO4) and 5-hydroxyindoleacetic acid (5-HIAA) were measured in the hippocampus and amygdala at 1 h after final stress condition, respectively.
RESULTS
Immobility time and corticosterone levels were significantly increased in both the physical and psychological stress groups compared to the control group. The administration of VE significantly reduced these parameters in both the physical and psychological stress groups. In addition, compared to the control group, physical and psychological stress groups showed significantly increased levels of MHPG-SO4 and 5-HIAA in the hippocampus and amygdala, respectively. The administration of VE significantly suppressed the increase of MHPG-SO4 and 5-HIAA in the two stress groups.
CONCLUSION
These results suggest that VE can suppress physical and psychological stress responses by modulating the changes in 5-HT and NE turnover in the hippocampus and amygdala.
Topics: Amygdala; Animals; Biogenic Monoamines; Brain; Corticosterone; Electroshock; Hippocampus; Male; Methoxyhydroxyphenylglycol; Mice; Mice, Inbred ICR; Neurotransmitter Agents; Norepinephrine; Pain; Phytotherapy; Plant Extracts; Plant Roots; Serotonin; Stress, Physiological; Stress, Psychological; Swimming; Valerian
PubMed: 25495725
DOI: 10.1186/1472-6882-14-476 -
PloS One 2014The brain stem auditory system of the chick is an advantageous model for examining changes that occur as a result of deafness. Elimination of acoustic input through...
The brain stem auditory system of the chick is an advantageous model for examining changes that occur as a result of deafness. Elimination of acoustic input through cochlear ablation results in the eventual death of approximately 30% of neurons in the chick cochlear nucleus, nucleus magnocellularis (NM). One early change following deafness is an alteration in NM ribosomes, evidenced both by a decrease in protein synthesis and reduction in antigenicity for Y10B, a monoclonal antibody that recognizes a ribosomal epitope. Previous studies have shown that mGluR activation is necessary to maintain Y10B antigenicity and NM viability. What is still unclear, however, is whether or not mGluR activation is sufficient to prevent deafness-induced changes in these neurons, or if other activity-dependent factors are also necessary. The current study investigated the ability of mGluR activation to regulate cochlear nucleus ribosomes in the absence of auditory nerve input. In vitro methods were employed to periodically pressure eject glutamate or mGluR agonists over neurons on one side of a slice preparation leaving the opposite side of the same slice untreated. Immunohistochemistry was then performed using Y10B in order to assess ribosomal changes. Application of glutamate and both group I and II selective mGluR agonists effectively rescued ribosomal antigenicity on the treated side of the slice in comparison to ribosomes on the untreated side. These findings suggest that administration of mGluR agonists is sufficient to reduce the early interruption of normal ribosomal integrity that is typically seen following loss of auditory nerve activity.
Topics: Animals; Brain Stem; Bridged Bicyclo Compounds; Chickens; Cochlear Nerve; Cochlear Nucleus; Deafness; Epitope Mapping; Glutamic Acid; Humans; Methoxyhydroxyphenylglycol; Protein Biosynthesis; Receptors, Metabotropic Glutamate; Ribosomes
PubMed: 25334004
DOI: 10.1371/journal.pone.0111243 -
Scientific Reports Jan 2015Memory is fixed solidly by repetition. However, the cellular mechanism underlying this repetition-dependent memory consolidation/reconsolidation remains unclear. In our...
Memory is fixed solidly by repetition. However, the cellular mechanism underlying this repetition-dependent memory consolidation/reconsolidation remains unclear. In our previous study using stable slice cultures of the rodent hippocampus, we found long-lasting synaptic enhancement/suppression coupled with synapse formation/elimination after repeated inductions of chemical LTP/LTD, respectively. We proposed these phenomena as useful model systems for analyzing repetition-dependent memory consolidation. Recently, we analyzed the dynamics of dendritic spines during development of the enhancement, and found that the spines increased in number following characteristic stochastic processes. The current study investigates spine dynamics during the development of the suppression. We found that the rate of spine retraction increased immediately leaving that of spine generation unaltered. Spine elimination occurred independent of the pre-existing spine density on the dendritic segment. In terms of elimination, mushroom-type spines were not necessarily more stable than stubby-type and thin-type spines.
Topics: Animals; Dendritic Spines; Fluorescent Dyes; Hippocampus; In Vitro Techniques; Long-Term Potentiation; Methoxyhydroxyphenylglycol; Mice; Mice, Transgenic; Microscopy, Confocal; Synapses; Time Factors
PubMed: 25573377
DOI: 10.1038/srep07707 -
Nutrients Dec 2018Hops, the immature inflorescences of the female hop plant ( L.) are one of the main components of beer and provides flavor and bitterness. β-Eudesmol, an oxygenated... (Randomized Controlled Trial)
Randomized Controlled Trial
β-Eudesmol, an Oxygenized Sesquiterpene, Reduces the Increase in Saliva 3-Methoxy-4-Hydroxyphenylglycol After the "Trier Social Stress Test" in Healthy Humans: A Randomized, Double-Blind, Placebo-Controlled Cross-Over Study.
Hops, the immature inflorescences of the female hop plant ( L.) are one of the main components of beer and provides flavor and bitterness. β-Eudesmol, an oxygenated sesquiterpene, is reported to accumulate in a particular hop cultivar. Recently, we revealed that β-Eudesmol ingestion affected autonomic nerve activity in an animal model. The effect on humans has not been elucidated, therefore, we investigated the effects of β-Eudesmol on reducing objective and subjective markers related to sympathetic nerve activity after the application of mental stress in healthy participants. Fifty participants (male and female aged 20 to 50 years) were randomly assigned to two groups. Five minutes before taking the Trier Social Stress Test (TSST) as a mental stressor, participants in each group ingested a beverage containing β-Eudesmol, the active beverage, or a placebo beverage that did not contain β-Eudesmol. Saliva 3-methoxy-4-hydroxyphenylglycol (MHPG), a major product of noradrenaline breakdown and a representative marker of sympathetic nerve activity, was significantly lower just after the TSST in the active group compared with the placebo group. Saliva cortisol, a marker of the endocrine stress response system, was not significantly different between the two groups. No adverse events related to test beverage ingestion were observed. This is the first experimental evidence of β-Eudesmol effect for mental stress in human.
Topics: Adult; Beverages; Cross-Over Studies; Double-Blind Method; Female; Healthy Volunteers; Humans; Humulus; Hydrocortisone; Male; Methoxyhydroxyphenylglycol; Middle Aged; Saliva; Sesquiterpenes, Eudesmane; Stress, Psychological; Young Adult
PubMed: 30577513
DOI: 10.3390/nu11010009 -
Molecular Brain Nov 2018Timing and temporal precision of action potential generation are thought to be important for encoding of information in the brain. The ability of single neurons to...
Timing and temporal precision of action potential generation are thought to be important for encoding of information in the brain. The ability of single neurons to transform their input into output action potential is primarily determined by intrinsic excitability. Particularly, plastic changes in intrinsic excitability represent the cellular substrate for spatial memory formation in CA1 pyramidal neurons (CA1-PNs). Here, we report that synaptically activated mGluR5-signaling can modulate the intrinsic excitability of CA1-PNs. Specifically, high-frequency stimulation at CA3-CA1 synapses increased firing rate and advanced spike onset with an improvement of temporal precision. These changes are mediated by mGluR5 activation that induces cADPR/RyR-dependent Ca release in the dendrites of CA1-PNs, which in turn causes an increase in persistent Na currents (I) in the dendrites. When group I mGluRs in CA1-PNs are globally activated pharmacologically, afterdepolarization (ADP) generation as well as increased firing rate are observed. These effects are abolished by inhibiting mGluR5/cADPR/RyR-dependent Ca release. However, the increase in firing rate, but not the generation of ADP is affected by inhibiting I. The differences between local and global activation of mGluR5-signaling in CA1-PNs indicates that mGluR5-dependent modulation of intrinsic excitability is highly compartmentalized and a variety of ion channels are recruited upon their differential subcellular localizations. As mGluR5 activation is induced by physiologically plausible brief high-frequency stimulation at CA3-CA1 synapses, our results suggest that mGluR5-induced enhancement of dendritic I in CA1-PNs may provide important implications for our understanding about place field formation in the hippocampus.
Topics: Action Potentials; Animals; CA1 Region, Hippocampal; Calcium; Cyclic ADP-Ribose; Dendrites; Electric Stimulation; Methoxyhydroxyphenylglycol; Rats, Sprague-Dawley; Receptor, Metabotropic Glutamate 5; Ryanodine Receptor Calcium Release Channel; Signal Transduction; Sodium Channels; Time Factors
PubMed: 30413218
DOI: 10.1186/s13041-018-0410-7 -
The European Journal of Neuroscience Aug 2019In several brain regions, ongoing metabotropic glutamate receptor 1 (mGlu1) transmission has been shown to tonically suppress synaptic levels of Ca -permeable AMPA...
In several brain regions, ongoing metabotropic glutamate receptor 1 (mGlu1) transmission has been shown to tonically suppress synaptic levels of Ca -permeable AMPA receptors (CP-AMPARs) while pharmacological activation of mGlu1 removes CP-AMPARs from these synapses. Consistent with this, we previously showed in nucleus accumbens (NAc) medium spiny neurons (MSNs) that reduced mGlu1 tone enables and mGlu1 positive allosteric modulation reverses the elevation of CP-AMPAR levels in the NAc that underlies enhanced cocaine craving in the "incubation of craving" rat model of addiction. To better understand mGlu1/CP-AMPAR interactions, we used a NAc/prefrontal cortex co-culture system in which NAc MSNs express high CP-AMPAR levels, providing an in vitro model for NAc MSNs after the incubation of cocaine craving. The non-specific group I orthosteric agonist dihydroxyphenylglycine (10 min) decreased cell surface GluA1 but not GluA2, indicating CP-AMPAR internalization. This was prevented by mGlu1 (LY367385) or mGlu5 (MTEP) blockade. However, a selective role for mGlu1 emerged in studies of long-term antagonist treatment. Thus, LY367385 (24 hr) increased surface GluA1 without affecting GluA2, whereas MTEP (24 hr) had no effect. In hippocampal neurons, scaling up of CP-AMPARs can occur through a mechanism requiring retinoic acid (RA) signaling and new GluA1 synthesis. Consistent with this, the LY367385-induced increase in surface GluA1 was blocked by anisomycin (translation inhibitor) or 4-(diethylamino)-benzaldehyde (RA synthesis inhibitor). Thus, mGlu1 transmission tonically suppresses cell surface CP-AMPAR levels, and decreasing mGlu1 tone increases surface CP-AMPARs via RA signaling and protein translation. These results identify a novel mechanism for homeostatic plasticity in NAc MSNs.
Topics: Animals; Benzoates; Calcium; Cells, Cultured; Excitatory Amino Acid Antagonists; Female; Glycine; Methoxyhydroxyphenylglycol; Mice; Mice, 129 Strain; Mice, Transgenic; Neurons; Nucleus Accumbens; Pregnancy; Protein Biosynthesis; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, Metabotropic Glutamate; Signal Transduction; Tretinoin
PubMed: 30222904
DOI: 10.1111/ejn.14151