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中国睡眠研究会第十一届全国学术年会

作者： Wei Xu Xiang-Shan Yuan Wei-Min Qu Zong-Yuan Hong Lu Wang Zhi-Li Huang School of Basic Medical Sciences State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science and Institutes of Brain Science Fudan University Laboratory of Quantitative Pharmacology Department of Pharmacology Wannan Medical College

Background Despite persistent clinical use for over 170 years, the neuronal mechanisms by which general anesthetics produce hypnosis remain unclear. Previous studies suggest that anesthetics exert hypnotic effects by acting on endogenous arousal circuits. Recently, it has been shown that the medial parabrachial nucleus（MPB） is a novel wake-promoting component in the dorsolateral pons. However, it is not known whether and how the MPB contributes to anesthetic-induced hypnosis. Methods The actions of sevoflurane, a widely used volatile anesthetic agent that best represents the drug class of halogenated ethers, were investigated in mice. The calcium signals of MPB neurons were examined using in vivo fiber photometry during sevoflurane exposure. The action potential firing, the membrane potential, the membrane input resistance, and the inhibitory postsynaptic currents mediated by GABAA receptors were recorded from MPB neurons using in vitro whole-cell patch-clamp recordings during infusion of sevoflurane. Results The population activities of MPB neurons were inhibited during sevoflurane anesthesia. Sevoflurane suppressed the firing rate of MPB neurons in a concentration-dependent and reversible manner. At a concentration of 0.22 mM, sevoflurane potentiated synaptic gabaa receptor-mediated inhibition, and the inhibitory effect of sevoflurane on the firing rate of MPB neurons was completely abolished by picrotoxin（100 μM）, a selective gabaa receptor antagonist. At a concentration of 0.44 mM, sevoflurane directly hyperpolarized MPB neurons and induced a significant decrease in membrane input resistance by increasing a basal potassium conductance. Conclusions Sevoflurane inhibits neurons in the MPB through postsynaptic GABAA receptors and background potassium channels, suggesting that the MPB is involved in sevoflurane-induced hypnosis.

关键词： sevoflurane GABAA receptors potassium channels medial parabrachial nucleus

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Fast and slow inhibition in the visual thalamus is influenced by allocating GABAA receptors with different gamma subunit identity to selective synapses

Fast and slow inhibition in the visual thalamus is influence...

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中国生理学会第24届全国会员代表大会暨生理学学术大会

作者：叶智文 Xiao Yu Catriona M Houston Zahra Aboukhalil William Foster Nicholas P Franks William Wisden Stephen G Brickley Imperial College London/Sleep anaesthesia and pain London SW7 2AZ

Cell-type specific differences in the kinetics of inhibitory postsynaptic conductances（IPSCs）impact upon network dynamics throughout the brain.Much attention has been focused on how gabaa receptor alpha and beta subunit diversity can influence IPSC kinetics,but little is known about the influence of different gamma subunits.We have examined whether gabaa receptor gamma subunit heterogeneity influences IPSC properties in the thalamus.The gamma2 subunit gene was deleted from GABAA receptors selectively in the dorsal lateral geniculate nucleus（d LGN）and whole-cell recording was then combined with imaging to enable a functional and morphological classification of relay neuron types.The removal of the gamma2 subunit from the d LGN reduced the overall s IPSC frequency across all relay cells and produced an absence of IPSCs in a subset of Y-type relay neurons.The remaining slower IPSCs associated with X-type relay neurons were both insensitive to diazepam and zinc indicating the absence of the gamma2 subunit.Because these slower IPSCs were potentiated by beta-carbolines,we propose these IPSCs involve gamma1 subunit-containing gabaa receptor activation.Therefore,gamma subunit heterogeneity appears to influence the kinetics of gabaa receptor-mediated synaptic transmission in the visual thalamus in a cell-type and synapse-selective manner.We suggest that d LGN GABAergic interneurons generate the slower IPSCs following activation of gamma1 subunit-containing GABAA receptors within X-type relay neurons.The reticular GABAergic input that generates the faster IPSCs involves activation of gamma2 subunit-containing GABAA receptors that dominate Y-type relay neurons.

关键词： thalamus vision synapse GABAA receptors inhibition

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3-Arylisothiazoloquinols as potent ligands for the benzodiazepine site of GABA_(A) receptors

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Journal of Biomedical Science and Engineering 2012年第1期5卷 1-9页

作者： Jakob Nilsson Elsebet Φstergaard Nielsen Tommy Liljefors Mogens Nielsen Olov Sterner Division of Organic Chemistry Lund UniversityLundSweden NeuroSearch A/S BallerupDenmark Faculty of Pharmaceutical Sciences University of CopenhagenCopenhagenDenmark

3-Arylisothiazolo[5,4-b]quinolin-4(9H)-ones and 3-arylisoxazolo[5,4-b]quinolin-4(9H)-ones were synthesized and assayed for affinity for the benzodiazepine binding site of the GABAA receptors. While the 3-arylisothiazoloquinolin-4-ones were found to be potent ligands, with affinities (expressed as the affinity Ki value) down to 1 nM, the 3-arylisoxazoloquinolin-4-ones are less potent. This is suggested to depend on sterical repulsive interaction of the 3-arylisoxazoloquinolin-4-ones with the receptor essential volume of the binding site, and a higher electron density at the nitrogen in the azole ring (N-2) as well as the carbonyl oxygen in the isothiazoloquinolin-4-ones enabling them to interact stronger with hydrogen bond donor sites at the binding site.

关键词： Isothiazolo[5,4-b]quinolin-4(9H)-ones Isoxazolo[5,4-b]quinolin-4(9H)-ones Benzodiazepine Binding Site GABAA receptors GABA_(A) Receptor Subtypes Pharmacophore Model

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Elevated Neurosteroids in the Lateral Thalamus Relieve Neuropathic Pain in Rats with Spared Nerve Injury

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Neuroscience Bulletin 2016年第4期32卷 311-322页

作者： Meng Zhang Jia Liu Meng-Meng Zhou Honghai Wu Yanning Hou Yun-Feng Li Yuxin Yin Lemin Zheng Feng-Yu Liu Ming Yi You Wan Neuroscience Research Institute Peking UniversityBeiiing 100191 China Institute of Systems Biomedicine Peking UniversityBeijing 100191 China Department of Pharmacy Bethune International PeaceHospital Shijiazhuang Shijiazhuang 050082 China Department of New Drug Evaluation Beijing Institute ofPharmacology and Toxicology Beijing 100007 China Institute of Cardiovascular Sciences and Institute of SystemsBiomedicine and Key Laboratory of MolecularCardiovascular Sciences of the Ministry of Education PekingUniversity Beijing 100191 China Key Laboratory for Neuroscience Ministry of Education/National Health and Family Planning Commission School ofBasic Medical Sciences Peking University Beijing 100191China Department of Neurobiology School of Basic MedicalSciences Peking University Beijing 100191 China

Neurosteroids are synthesized in the nervous system from cholesterol or steroidal precursors imported from peripheral sources. These compounds are important allosteric modulators of γ-aminobutyric acid A receptors （gabaaRs）, which play a vital role in pain modulation in the lateral thalamus, a main gate where somatosensory information enters the cerebral cortex. Using high-perfor mance liquid chromatography/tandem mass spectrometry, we found increased levels of neurosteroids （pregnenolone, progesterone, deoxycorticosterone, allopregnanolone, and tetrahydrodeoxycorticosterone） in the chronic stage of neuropathic pain （28 days after spared nerve injury） in rats.The expression of the translocator protein TSPO, the upstream steroidogenesis rate-limiting enzyme, increased at the same time. In vivo stereotaxic microinjection of neurosteroids or the TSPO activator AC-5216 into the lateral thalamus （AP -3.0 mm, ML 4-3.0 mm, DV 6.0 mm） alleviated the mechanical allodynia in neuropathic pain, while the TSPO inhibitor PK 11195 exacerbated it. The analgesic effects of AC-5216 and neurosteroids were sig- nificantly attenuated by the gabaaR antagonist bicuculline. These results suggested that elevated neurosteroids in the lateral thalamus play a protective role in the chronic stage of neuropathic pain.

关键词： Neurosteroids Translocator protein Sparednerve injury Thalamus GABAA receptors

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GABA UPTAKE BY GAT1 MODULATES LONG-TERM OPTICAL CHANGES FOLLOWING ELECTRICAL STIMULATION OF THE PITUITARY GLAND NEUROINTERMEDIATE LOBE

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Journal of Innovative Optical Health Sciences 2013年第3期6卷 46-57页

作者： P.KOSTERIN A.L.OBAID B.M.SALZBERG Department of Neuroscience Perelman School of Medicine University of Pennsylvania Philadelphia PA 19104 Department of Physiology Perelman School of Medicine University of Pennsylvania Philadelphia PA 19104

Intrinsic optical changes that follow infundibular stalk stimulation of the neurointermediate lobe of the mouse pituitary gland exhibit three different phases that reflect three distinct physiological events.The first(E-wave)is the rapid light-scattering increase that is associated with a nerve terminal volume increase(mechanical spike),and that accompanies excitation of the neurohy-pophysial terminals by the invading action potential;the second(S-wave)is the slower light-scattering decrease that is tightly corelated with the secretion of the peptide hormones oxytocin and arginine vasopressin,and the third is the long duration response(R-wave)that reflects cell volume changes in the pars interrmedia.We have studied the E-wave and the S-wave in earlier publications.The R-wave,considered here,is sensitive to chloride replacement as wel as to blockade of chloride channels.By blocking gabaa reeptors(which are ligand gated chloride channels)with pharrmacological agents,and by applying GABA directly into the bathing solution,or evoking its release from GABAergic inputs,we have demonstrated that this long-duration optical response is sensitive to chloride movements and reflects GABA-induced changes in the intrinsic optical propertis of the pars intermedia.The full time course of this optical response takes mimutes and,therefore,has to embody some other process(or processes)related to the restoration of resting physiological chloride concentrations,following the opening and closing of GABA A-reeptor channels.Here we demonstrate that the shape of the R wave,the longlasting light-scattering signal,is indeed affected by the activity of GAT1,one of the sodium-and.chloridedependent GA BA transporters.

关键词： Light scattering posterior pituitary pars nervosa neurohypophysis volume changes pars intermedic GABAA receptors

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Impairment of autophagic signaling in murine forebrain disrupts gabaa receptor trafficking leading to excitatoryinhibitory imbalance and ASD-like behaviours

Impairment of autophagic signaling in murine forebrain disru...

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中国神经科学学会第十二届全国学术会议

作者： Kelvin Hui Noriko Takashima Hiroshi Matsukawa Akiko Watanabe Per Nilsson Ryo Endo Takaomi Saido Shigeyoshi Itohara Takeo Yoshikawa Motomasa Tanaka Laboratory for Protein Conformation Diseases RIKEN Brain Science Institute Laboratory for Behavioral Genetics RIKEN Brain Science Institute Laboratory for Molecular Psychiatry RIKEN Brain Science Institute Laboroatory for Proteolytic Neuroscience RIKEN Brain Science Institute Department of Neurobiology Care Sciences and Society Karolinska Institutet

Many syndromic forms of autism spectrum disorder(ASD) are caused by mutations in proteins such as PTEN, TSC1, TSC2, and FMRP, which lie within the m TOR signaling pathway. While recent work has primarily focused on the dysregulation of protein translation via the deletion of these genes, few studies have examined how disruption of autophagy, another major downstream branch of m TOR signaling,contributes to neuronal dysfunction and ASD pathogenesis. To this end, we and others have previously examined mice deficient for autophagy in forebrain excitatory neurons via the deletion of Atg7 by Ca MKII-cre and observed ASD-like behavioural abnormalities in addition to neuronal dysfunctions from the molecular to the network level. As ASD is believed to be caused by an imbalance between excitatory and inhibitory signals in the brain, we have further extended our analysis to examine disruption of autophagy in forebrain GABAergic interneurons. Similar to disrupted autophagy in other neuronal and non-neuronal cell types, Atg7 deletion by Dlx5-cre results in time-dependent ubiquitin+ and p62+ aggregate formation in affected neurons. Notably, Dlx5-cre Atg7 c KO mice exhibit an overlapping set of ASD-like behavioural abnormalities previously observed in Ca MKII-cre Atg7 c KO animals. Furthermore, we have detected a disruption of the excitatory-inhibitory balance in both Ca MKII-cre and Dlx5-cre Atg7 c KO mice. Using primary cultured neurons, a specific reduction of surface GABAA receptors was observed in Atg7 c KO neurons. Unbiased mass spectrometric and subsequent antibody-based analyses demonstrated that members of the GABARAP(GABA receptor-associated protein) protein family accumulate and mislocalize to p62+ aggregates formed in affected neurons of both Ca MKII-cre and Dlx5-cre Atg7 c KO brains. Genetic manipulation of GABARAP family proteins and p62 in wild-type or Atg7 c KO neurons further revealed that gabaa receptor trafficking are influenced by p62 aggregates as they interact with and sequester GABARAP family proteins. F

关键词： autophagy autism protein aggregation GABAA receptors GABARAP

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Sevoflurane Depresses Neurons in the Medial Parabrachial Nucleus of mice

Sevoflurane Depresses Neurons in the Medial Parabrachial Nuc...

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中国睡眠研究会第十届全国学术年会

作者： Wei Xu Tian-Xiao Wang Zhi-Li Huang Zong-Yuan Hong Lu Wang Department of Pharmacology State Key Laboratory of Medical NeurobiologySchool of Basic Medical SciencesShanghai Medical College of Fudan University Laboratory of Quantitative Pharmacology Wannan Medical College

Purpose: Recently,it has been shown that the medial parabrachial nucleus（MPB） is a novel wake-promoting component in the dorsolateral pons.In the present study,whether the MPB contributes to the anesthetic-induced hypnosis was to investigated.Methods: The actions of sevoflurane were investigated in acute pons slices containing the MPB prepared from adult mice.The action potential firing,the membrane potential,the membrane input resistance,and the inhibitory postsynaptic currents mediated by GABAA receptors were recorded from MPB neurons using whole-cell patch-clamp recordings during infusion of sevoflurane.Results:Sevoflurane suppressed the firing rate of MPB neurons in a concentration-dependent and reversible manner.At a concentration of 0.8 mM,sevoflurane potentiated synaptic gabaa receptor-mediated inhibition,and the inhibitory effect of sevoflurane on the firing rate of MPB neurons was completely abolished by picrotoxin（100 μM）,which is a selective gabaa receptor antagonist.At a concentration of 2.4 mM,sevoflurane directly hyperpolarized MPB neurons and induced a significant decrease in membrane input resistance by increasing a basal potassium conductance.Conclusion: Sevoflurane acts on and inhibits neurons in the MPB through postsynaptic GABAA receptors and background potassium channels,which suggests that the MPB is involved in the sevoflurane-induced hypnosis in mice.

关键词： GABAA receptors medial parabrachial Nucleus potassium channels sevoflurane

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Cortical disinhibition as a mechanism of chronic pain

Cortical disinhibition as a mechanism of chronic pain

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中国神经科学学会第四次会员代表大会暨第八届全国学术会议

作者： Neng GONG~#,Wen ZHANG~#,Tian-Le XU~* Institute of Neuroscience and Key Laboratory of Neurobiology,Shanghai Institutes for Biological Sciences,Chinese Academy of Sciences,Shanghai 200031,China

The anterior cingulate cortex(ACC) is implicated in supraspinal nociceptive processing.Recent evidence suggests that excitatory synaptic efficacy in the ACC is enhanced during chronic pain.However,little is known about the modulation of inhibitory transmission in the ACC.In this study,we investigated the alterations of GABAergic synapse in the ACC during persistent inflammatory pain by electrophysiological and biochemical methods.Here,we show that peripheral inflammation reduced both the amplitudes and frequencies of GABAergic postsynaptic currents in the ACC at 7 day after complete Freund’s adjuvant(CFA) injection.Meanwhile,the expression of GABAA receptors(gabaaRs) in the ACC was decreased.Interestingly,at 14 days but not 7 days after CFA injection,we also observed the downregulation of potassium chloride cotransporter-2(KCC2),the key Cl extrusion mechanism responsible for the low intracellular Cl concentration,and the elevation of Cl reversal potential in the ACC.These results indicate the occurrence of GABAergic disinhibition in the ACC with multiple mechanisms during chronic pain.Furthermore,selective inhibition of gabaaR and KCC2 in the ACC elevated the pain responses to noxious heat stimuli in naive rats,while enhancing gabaaR function in the ACC attenuated the hyperalgesia of inflamed rats.Taken together,our results suggest that GABAergic disinhibition in the ACC during chronic pain is a novel mechanism in the cortical processing of nociception,and further underscore the importance of excitation-inhibition balance in the maintenance of cortical network activity.

关键词： GABAergic disinhibition GABAA receptors potassium chloride cotransporter-2 anterior cingulate cortex chronic pain hyperalgesia

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