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FBXL4 serves as a clock output molecule to regulate sleep through promoting gabaa receptor degradation

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FBXL4 serves as a clock output molecule to regulate sleep th...

Contribution of gabaa receptor-mediated activity to self-generated oscillations in hippocampal CA3-CA1 regions

中国神经科学学会第十二届全国学术会议

作者： Qian LI Yi LI Xiao WANG Junxia QI Huawei TONG Zikai ZHOU Zi Chao ZHANG Junhai HAN Institute of Life Sciences the Key Laboratory of Developmental Genes and Human Disease Southeast University

Sleep is tightly governed by the circadian clock that contains a negative transcriptional feedback loop and synchronizes the physiology and behavior of most animals to daily environmental oscillations. In both vertebrates and invertebrates, the status of sleep and wake is controlled by the electrical activity of pacemaker neurons, which is circadian-regulated and suppressed by inhibitory GABAergic inputs. However, how the circadian clock rhythmically regulates the activity of pacemaker neuron is unclear. Here, we show that the level of Drosophila GABA receptor Resistant to Dieldrin(RDL) undergoes a daily cycle in wake-promoting large ventral lateral neurons(l-LNvs) and identify the E3 ligase Fbxl4 as a clock output molecule promoting RDL poly-ubiquitination and degradation. Depletion of Fbxl4 results in RDL accumulation, shortened sleep onset, and increased sleep time both in the day and the night. Moreover, we reveal that the expression of Fbxl4 in l-LNvs is Clock dependent but fbxl4 mutants exhibit normal locomotor rhythms. Thus, our study uncovers the critical molecular linkage between circadian clock and the electrical activity of pacemaker neurons and demonstrates that clock-dependent Fbxl4 expression downregulates gabaa receptor to increase the activity of pacemaker neurons and promote wakefulness.

关键词： Sleep circadian clock gabaa receptor E3 ligase Fbxl4 degradation

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Contribution of GABAA receptor-mediated activity to self-gen...

A novel positive modulator of GABA_(A) receptor exhibiting antidepressive properties

中国神经科学学会第九届全国学术会议暨第五次会员代表大会

作者： Yan YANG,Xiao-Lin XUE,Chao DING,Zhi-Ru WANG~* Plasticity of Neural Circuit Lab,Key Laboratory of Brain Functional Genomics,Ministry of Education,East China Normal University,Shanghai 200062,China

Objective Spontaneous oscillations in the hippocampus are believed to play important roles in hippocampus-dependent cognition and learning and *** studies in hippocampal slices indicate that these oscillations are mediated by the activity of intemeurons in the hippocampus,particularly via gabaa receptors. This issue remains to be further *** In this study,we developed a new system of in vitro wholecell patch-clamp recordings in whole-hippocampus *** In such preparation,robust spontaneous oscillations(from 0.8 Hz to 2 Hz)were observed in both pyramidal cells and intemeurons in the absent of any *** whole-cell recordings further revealed that the oscillations were synchronized in CA1, CA3,and across CA1-CA3 *** the presence of bicuculline-a GABA receptor blocker-in bath solution,the frequency of spontaneous oscillations was remarkably reduced to 0.1-0.2 Hz,which was found in the pyramidal cells and intemeurons of both CA1 and CA3 ***,extracellular blockade of GABA receptors by SCH50911 didn’t alter the frequency of the *** treatment of ZD7288,which blocks hyperpolarization-activated (I)channels,also slowed down the hippocampal oscillations to .4 *** Our observations from whole-hippocampus formation revealed the important roles of GABA receptors,probably coordinating with the activity of I channels,in mediating the self-generated oscillations in the hippocampus in the absence of extrahippocampus inputs.

关键词： hippocampus oscillation gabaa receptor Ih channel

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生理学报 2024年第5期76卷 677-690页

作者： ZHENG Yin-Li SHEN Fu-Yi WANG Yang PAN Jing-Pei WANG Xian LI Tian-Yu DU Wei-Jia LIU Zhi-Qiang LI Yang GUO Fei School of Pharmacy Anhui University of Chinese MedicineHefei 230012China Shanghai Key Laboratory of Maternal Fetal Medicine Shanghai Institute of Maternal-Fetal Medicine and Gynecologic OncologyDepartment of AnesthesiologyShanghai First Maternity and Infant HospitalTongji University School of MedicineShanghai 201204China Wuya College of Innovation Shenyang Pharmaceutical UniversityShenyang 110016China State Key Laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China School of Chinese Materia Medica Nanjing University of Chinese MedicineNanjing 210023China Anesthesia and Brain Function Research Institute Tongji University School of MedicineShanghai 200082China

γ-Aminobutyric acid(GABA) neurotransmission alterations have been implicated to play a role in depression pathogenesis. While GABA_(A) receptor positive allosteric modulators are emerging as promising in clinical practice, their precise antidepressant mechanism remains to be further elucidated. The aim of the present study was to investigate the effects of LY-02, a novel compound derived from the metabolite of timosaponin, on depression in animals and its mechanism. The results of behavioral tests showed that LY-02 exhibited better antidepressant effects in both male C57BL/6 mice and Sprague Dawley(SD) rats. The results of cellular voltage clamp experiments showed that LY-02 enhanced GABA-mediated currents in HEK293T cells expressing recombinant α6β3δ subunitcontaining GABA_(A) receptors. Electrophysiological recording from brain slices showed that LY-02 decreased the amplitude of spontaneous inhibitory postsynaptic current(sIPSC) and increased action potentials of pyramidal neurons in the medial prefrontal cortex(mPFC) of C57BL/6 mice. Western blot results showed that LY-02 dose-dependently up-regulated the protein expression levels of brain-derived neurotrophic factor(BDNF), tropomyosin related kinase B(TrkB) and postsynaptic density protein 95(PSD-95) in m PFC of mice. The above results suggest that LY-02, as a positive modulator of GABA_(A) receptors, reduces inhibitory neurotransmission in pyramidal neurons. It further activates the BDNF/TrkB signaling pathway, thus exerting antidepressant effects. It suggests that LY-02 is a potential novel therapeutic agent for depression treatment.

关键词： antidepressant gabaa receptor positive modulator neurotransmission

Heterologous Expression of Rat Testis GABA_A receptor β3t Splicing Variant in CHO Cells

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Journal of Reproduction and Contraception 2004年第3期15卷 131-138页

作者： Shi-feng LI Yu-guang CHEN Yuan-chang YAN Yi-ping LI Institute of Biochemistry and Cell Biology Shanghai Institute of Biological Sciences Chinese Academy of Sciences Shanghai 200031 China College of Life Science Shanghai University Shanghai 200436 China

Objective To characterize a possible retention function of unique sequence in the 5＇end of rat testis gabaa receptor β3t splicing variant Methods Rat testis gabaa receptor β3t splicing variant cDNA was cloned and two eukaryotic expression recombinant plasmids of pEGFP-N1 and pEGFP-C1 were constructed respectively by fusing green fluorescent protein to the N or C-terminus of β3t isoform. The recombinant plasmids were transfected into CHO cells by calcium phosphate co-precipitation method Fluorescence microscope and laser confocal microscope were used to analyze localization of β3t in the transfected cells. ConA-Texas-Red was used to label cell ER and the localization of rat testis β3t splicing variant in CHO cells was determined. Results When rat testis β3t splicing variant was expressed in CHO cells, two expression patterns were delineated, the distributions of uniform and mainly discrete intracellular compartments respectively, The chimera product failed to be translocated into the cell surface when expressed in ClIO cells; whereas the β3 subunit of rat brain was incorporated into the plasma membrane. Conclusion The inability of β3t to target into the ER may be a consequence of the unique 25 specific amino acid segments in the N terminus.

关键词： gabaa receptor β3t splicing variant heterologous expression CHO cell

Enhancement of GABA_A receptor-Mediated Inhibitory Postsynaptic Currents Induced by "Partial Oxygen-Glucose Deprivation"

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Zoological Research 2007年第5期28卷 491-496页

作者：李红斌韩会丽马文裴董志芳徐林中国科学院昆明动物研究所学习与记忆室

Oxygen/glucose deprivation （OGD） has been widely used as an in vitro model of focal ischemia, where the blood flow is severely reduced and neurons rapidly die. However, adjacent to the focal region is ‘penumbra＇, where residual blood flow remains oxygen and glucose supplies are at low levels. To model this pathological genesis, we developed a partial OGD （pOGD） protocol in a rat brain slice. This model met two requirements： oxygen was partially deprived and glucose was reduced in the perfusion buffer. Therefore we investigated the effect of pOGD on gama-aminobutyric acid （gabaa） receptor-mediated inhibitory postsynaptic currents （IPSCs） in CA1 neurons of a hippocampal slice through whole-cell patch-clamp technique. We found that the amplitude and decay time of IPSCs were increased immediately during pOGD treatment. And the enhancement of IPSCs amplitude resulted from an increase of the synaptic conductance without a significant change in the reversal potential of chloride. These results suggested that the nervous system could increase inhibitory neurotransmission to offset excitation by homeostasis mechanisms during the partial oxygen and glucose attack.

关键词： Partial oxygen-glucose deprivation (pOGD) gabaa receptor IPSCs Amplitude Decay time

PKCε Mediates Substance P Inhibition of GABA_A receptors-Mediated Current in Rat Dorsal Root Ganglion

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2015年第1期35卷 1-9页

作者：李丽赵磊王洋马克涛石文艳王英姿司军强 Department of Physiology Medical College of Shihezi University Key Laboratory of Xinjiang Endemic and Ethnic Disease Shihezi University School of Medicine Basic Medical School of Wuhan University Basic Medical School Tongji Medical College Huazhong University of Science and Technology

The mechanism underlying the modulatory effect of substance P（SP） on GABA-activated response in rat dorsal root ganglion（DRG） neurons was investigated. In freshly dissociated rat DRG neurons, whole-cell patch-clamp technique was used to record GABA-activated current and sharp electrode intracellular recording technique was used to record GABA-induced membrane depolarization. Application of GABA（1–1000 μmol/L） induced an inward current in a concentration-dependent manner in 114 out of 127 DRG neurons（89.8 %） examined with whole-cell patch-clamp recordings. Bath application of GABA（1–1000 μmol/L） evoked a depolarizing response in 236 out of 257（91.8%） DRG neurons examined with intracellular recordings. Application of SP（0.001–1 μmol/L） suppressed the GABA-activated inward current and membrane depolarization. The inhibitory effects were concentration-dependent and could be blocked by the selective neurokinin 1（NK1） receptors antagonist spantide but not by L659187 and SR142801（1 μmol/L, n=7）, selective antagonists of NK2 and NK3. The inhibitory effect of SP was significantly reduced by the calcium chelator BAPTA-AM, phospholipase C（PLC） inhibitor U73122, and PKC inhibitor chelerythrine, respectively. The PKA inhibitor H-89 did not affect the SP effect. Remarkably, the inhibitory effect of SP on GABA-activated current was nearly completely removed by a selective PKCε inhibitor epilon-V1-2 but not by safingol and LY333531, selective inhibitors of PKCα and PKCβ. Our results suggest that NK1 receptor mediates SP-induced inhibition of GABA-activated current and membrane depolarization by activating intracellular PLC-Ca2＋-PKCε cascade. SP might regulate the excitability of peripheral nociceptors through inhibition of the ＂pre-synaptic inhibition＂ evoked by GABA, which may explain its role in pain and neurogenic inflammation.

关键词： peripheral nervous system substance P gabaa receptor protein kinase C dorsal root ganglion

GABAergic Interneurons are Required for Generation of Slow CA1 Oscillation in Rat Hippocampus

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Neuroscience Bulletin 2016年第4期32卷 363-373页

作者： Yuan Xu Lidan Wang Yu-zhang Liu Yan Yang Xiaolin Xue Zhiru Wang Institute and Key Laboratory of Brain Functional Genomics of The Ministry of Education of China Shanghai Key Laboratory of Brain Functional GenomicsSchool of Life Sciences East China Normal University

Neuronal oscillations are fundamental to hip- pocampal function. It has been shown that GABAergic interneurons make an important contribution to hippocampal oscillations, but the underlying mechanism is not well understood. Here, using whole-cell recording in the complete hippocampal formation isolated from rats at postnatal days 14-18, we showed that gabaa receptormediated activity enhanced the generation of slow CA1 oscillations. In vitro, slow oscillations （0.5-1.5 Hz） were generated in CA1 neurons, and they consisted primarily of excitatory rather than inhibitory membrane-potential changes. These oscillations were greatly reduced by blocking gabaa receptor-mediated activity with bicuculline and were enhanced by increasing such activity with midazolam, suggesting that interneurons are required for oscillation generation. Consistently, CA1 fast-spiking interneurons were found to generate action potentials usually preceding those in CA1 pyramidal cells. These findings indicate a gabaa receptor-based mechanism for the generation of the slow CA1 oscillation in the hippocampus.

关键词： Hippocampus - Oscillation SynchronizationGABAergic interneuron gabaa receptor

The key roles of 5’Ile in the binding of fipronil with gabaa receptors from fruitfly and zebrafish,revealed by molecular dynamic studies

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The key roles of 5’Ile in the binding of fipronil with GABA...

Oligodendroglial GABAergic Signaling:More Than Inhibition!

第八届全国化学生物学学术会议

作者：郑楠张薇李忠程家高 Shanghai Key Laboratory of Chemical Biology School of PharmacyEast China University of Science and Technology

＜正＞Fipronil,which act on insect gabaa receptor was an important insecticide for crop ***,the observed high toxicity on fish deeply limited its *** understanding the binding mode of fipronil with the different gabaa... 详细信息

关键词： gabaa receptor Fipronil Molecular dynamics simulation

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Neuroscience Bulletin 2021年第7期37卷 1039-1050页

作者： Xianshu Bai Frank Kirchhoff Anja Scheller Molecular Physiology Center for Integrative Physiology and Molecular Medicine(CIPMM)University of Saarland66421 HomburgGermany

GABA is the main inhibitory neurotransmitter in the CNS acting at two distinct types of receptor:ligand-gated ionotropic gabaa receptors and G protein-coupled metabotropic GABAB receptors,thus mediating fast and slow inhibition of excitability at central *** signal transmission has been intensively studied in neurons in contrast to oligodendrocytes and their precursors(OPCs),although the latter express both types of GABA *** studies focusing on interneuron myelination and interneuron-OPC synapses have shed light on the importance of GABA signaling in the oligodendrocyte *** this review,we start with a short summary on GABA itself and neuronal GABAergic ***,we elaborate on the physiological role of GABA receptors within the oligodendrocyte lineage and conclude with a description of these receptors as putative targets in treatments of CNS diseases.

关键词： GABA gabaa receptor GABAB receptor OPC Oligodendrocyte lineage