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Dissertations / Theses on the topic 'GABA'

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Published: 4 June 2021
Last updated: 9 June 2025

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1

Kragler, Andrea. "GABA-Transporter." Diss., lmu, 2003. http://nbn-resolving.de/urn:nbn:de:bvb:19-9774.

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2

Picard, Raymonde. "Charakterisierung funktioneller Domänen für GABA und Furosemid auf GABAA-Rezeptoren." [S.l.] : [s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=971995141.

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3

Ong, Jennifer. "GABA and GABA-receptors in the enteric nervous system /." Title page, contents and summary only, 1985. http://web4.library.adelaide.edu.au/theses/09PH/09pho582.pdf.

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4

Davies, Martin. "The GABA transporter and the regulation of the GABA¦A receptor." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1993. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/nq23915.pdf.

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5

Aanesen, Arthur. "Gaba and human spermatozoa : characterization and regulation of gaba transport proteins /." Stockholm, 1998. http://diss.kib.ki.se/search/diss.se.cfm?19980925aane.

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6

Mendu, Suresh Kumar. "Role of GABA and GABAA Channels in T lymphocytes and Stem cells." Doctoral thesis, Uppsala universitet, Institutionen för neurovetenskap, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-172541.

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GABA (gamma-aminobutyric acid) is best known for its physiological function in the central nervous system.  In the brain GABA is the main inhibitory neurotransmitter where it decreases excitability of neurons and neuronal networks.  The balance between excitation evoked by glutamate and inhibition evoked by GABA is the base from where the brain works. It is fair to say that glutamate is like the gas-pedal and GABA the brake that keeps the brain running at a normal speed.  But, it is not only in the brain that GABA is taking a part in a physiological process vital to life. GABA is present in blood and is even released in the pancreatic islets. What function GABA has in these tissues is still being examined and is the focus of this thesis. The GABA concentration in the peripheral tissues is in the submicromolar concentration range.  The studies in this thesis support the idea that GABA reduces the proliferation and cytokine secretion from immune cells by activating high-affinity GABAA channels in the cells. In contrast, in retinal progenitor stem cells GABA promotes cell proliferation.  These studies demonstrate that the effect of GABA on proliferation is cell-type specific. The GABAA channel subunit isoforms expressed in human, mice and rats T cells differ between the species.  This interspecies variability will result in different pharmacological profile of the subtypes of GABAA channels expressed whereas the physiological process most likely is the same.  Clearly, GABA is not only a neurotransmitter molecule but is also an immunomodulator and an important signal molecule in peripheral tissues.
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7

Gardner-Fortier, Catherine. "Développement d'un fromage fonctionnel renfermant un composé bioactif, l'acide gama-aminobutyrique (GABA)." Thesis, Université Laval, 2011. http://www.theses.ulaval.ca/2011/28143/28143.pdf.

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8

CHAMBON, JEAN-PIERRE. "Caracterisation de derives pyridazinyl-gaba comme ligands antagonistes du recepteur gaba-a." Université Louis Pasteur (Strasbourg) (1971-2008), 1987. http://www.theses.fr/1987STR13002.

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9

Chambon, Jean-Pierre. "Caractérisation de dérivés pyridazinyl-gaba comme ligands antagonistiques du récepteur gaba-A." Grenoble 2 : ANRT, 1987. http://catalogue.bnf.fr/ark:/12148/cb37603758b.

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10

Namwindwa, Ernest Sinvula. "GABA and glutamate mimetics." Thesis, University of Bath, 1987. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.376436.

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11

Babateen, Omar M. "GABA signaling regulation by GLP-1 receptor agonists and GABA-A receptors modulator." Doctoral thesis, Uppsala universitet, Fysiologi, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-282431.

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GABA (γ-aminobutyric acid) is the main neuroinhibitory transmitter in mammalian brains.  It binds to GABA-A and GABA-B receptors. The GABA-A receptors are ligand-gated chloride channels. A variety of GABA-A receptor agonists and antagonists have been developed to study the GABA-mediated inhibition and to explore new medications. In this thesis I have examined the role of GABA in brain tumors and the effects of the metabolic hormone GLP-1 on GABAergic signaling in neurons. I studied if GABA-A receptors subunits were expressed and formed functional ion channels in the glioblastoma cell line U3047MG. I identified the mRNA of 11, α2, α3, α5, β1, β2, β3, δ, γ3, π, θ and ρ2, out of the 19 known GABA-A subunits. Immunostaining demonstrated abundant expression of the α3 and β3 subunits. Interestingly, whole-cell GABA-activated currents were recorded in only 12% of the cells. The GABA-activated currents half-maximal concentration (EC50) was 36 µM. The currents were modulated by diazepam (1 µM) and the general anesthetics propofol (50 µM) and etomidate (EC50 = 50 nM). GLP-1 and exendin-4 transiently enhanced the GABA-A receptor-mediated currents in CA3 neurons of the rat hippocampus. The tonic and the spontaneous inhibitory postsynaptic currents increased as compared to control in a concentration dependent manner.  The increase was related to enhanced release of GABA from the presynaptic terminals and increased insertion or affinity of GABA-A receptors in the CA3 postsynaptic neuron. In contrast to GLP-1 and exendin-4, liraglutide enhanced the currents only in a subset of the neurons and the effect was mainly mediated by presynaptic mechanisms.  In conclusion, GABA signaling in neurons is modified by the metabolic hormone GLP-1 and its mimetics highlighting the important cross-talk that takes place between the brain and other organs. Medicines modifying GABA signaling in the brain may be important for a number of diseases.
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12

Ferguson, Shane C. D. J. "GABA and retino-tectal development." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0019/MQ55206.pdf.

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13

Tabor, Alethea Bernice. "Synthesis of GABA-T inhibitors." Thesis, University of Cambridge, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.305797.

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14

Hosie, Alastair Marshall. "GABA receptors of Drosophila melanogaster." Thesis, University of Cambridge, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.324973.

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15

Ali, Saima. "Regulation of the cell surface expression and the function of GABA¦BR1a by GABA¦BR2." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0027/MQ50433.pdf.

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16

Chen, Jianping. "The Effects of Chronic Ethanol Intake on the Allosteric Interaction Between GABA and Benzodiazepine at the GABAA Receptor." Thesis, University of North Texas, 1992. https://digital.library.unt.edu/ark:/67531/metadc501231/.

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This study examined the effects of chronic ethanol intake on the density, affinity, and allosteric modulation of rat brain GABAA receptor subtypes. In the presence of GABA, the apparent affinity for the benzodiazepine agonist flunitrazepam was increased and for the inverse agonist R015-4513 was decreased. No alteration in the capacity of GABA to modulate flunitrazepam and R015-4513 binding was observed in membranes prepared from cortex, hippocampus or cerebellum following chronic ethanol intake or withdrawal. The results also demonstrate two different binding sites for [3H]RO 15-4513 in rat cerebellum that differ in their affinities for diazepam. Chronic ethanol treatment and withdrawal did not significantly change the apparent affinity or density of these two receptor subtypes.
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17

Rahman, Mozibur. "Effects of neuroactive steroids on the recombinant GABAA receptor in Xenopus oocyte." Doctoral thesis, Umeå : Univ, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1112.

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18

Ebrik-Al, Akoum Sahar. "Nouveaux ligands du récepteur gaba b, nouvelles pyrrolidin-2-ones : études chimique et pharmacologique." Lille 2, 1995. http://www.theses.fr/1995LIL2P261.

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19

ANSAR, M'HAMMED. "Agonistes et antagonistes de l'acide gamma-aminobutyrique au niveau du recepteur gaba-b : etudes chimique et pharmacologique." Lille 2, 1995. http://www.theses.fr/1995LIL2P251.

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20

Mortensen, Martin. "GABAa receptor pharmacology : electrophysiological studies of agonist activity on reconstituted human GABAa receptors /." [Cph.] : Department of Pharmacology, The Royal Danish School of Pharmacy, 2002. http://www.dfh.dk/phd/defences/martinmortensen.htm.

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21

BOUCHET, MARIE-JEANNE. "Marquage irreversible du recepteur gaba#a." Université Louis Pasteur (Strasbourg) (1971-2008), 1996. http://www.theses.fr/1996STR13281.

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L'objectif de notre recherche est le marquage irreversible du site de liaison de l'acide -aminobutyrique (gaba#a) en vue de sa caracterisation moleculaire. Le recepteur ionotrope gaba#a est un hetero-oligomere regroupant autour d'un canal chlorure plusieurs sites de liaison qui interagissent entre eux: gaba, benzodiazepine, canal, barbiturates, steroides, ainsi que d'autres moins bien definis. Le recepteur gaba#a aurait une structure pentamerique, composee d'au moins trois des seize sous-unites ( 1-6, 1-4, 1-3, , p1-2) que la biologie moleculaire a permis mettre en evidence a ce jour, sans qu'une (ou des) composition(s) definie(s) aient pu etre attribuees aux recepteur(s) natif(s) qui possede(nt) vraissemblablement une grande heterogeneite de constitution. La pharmacologie complexe du recepteur gaba#a, probablement liee a sa structure moleculaire, pourra etre mieux comprise lorsque les proteines receptrices auront ete caracterisees et la topologie des differents sites de liaison mieux cernee: c'est le but du marquage irreversible qui consiste a etablir une liaison covalente entre le recepteur et un ligand portant une fonction reactive en l'absence (marquage d'affinite) ou en presence de lumiere (marquage de photoaffinite). Nous avons synthetise une quinzaine de molecules photoactivables portant quatre fonctions photosensibles differentes. Trois d'entre elles ont ete retenues en fonction de leurs caracteristiques physico-chimiques, de leur stabilite en milieu physiologique et de leur affinite pour le recepteur: l'acide 2-diazo-4-(5)-imidazole acetique 35, le chlorure de m-sulfonate benzene diazonium (msbd) 41 et l'azidopyridazinyl-gaba 49 sont des marqueurs irreversibles du recepteur gaba#a. Les deux derniers ont ete retenus pour etre synthetises sous forme radioactive en raison de leur stabilite en presence du recepteur membranaire. L'azidopyridazinyl-gaba 49 (ic#5#0=6. 10#-#7 m) est un marqueur de photoaffinite efficace dont l'analogue radioactif permettra une etude topologique du recepteur par marquage de la proteine et sequencage des elements proteolyses et purifies. Le msbd est un marqueur d'affinite puissant dont le caractere d'antagoniste non-competitif a ete mis en evidence par electrophysiologie. Une methode de dissociation efficace a permis de caracteriser sa liaison irreversible avec le recepteur gaba#a membranaire par etude des cinetiques de marquage et d'acceder ainsi a sa constante de dissociation. Le radioligand #3hmsbd marque quatre bandes proteiques dont le poids moleculaire correspond a celui de sous-unites et du recepteur. Le msbd pourra, en raison de ses caracteristiques d'affinite, etre utilise soit sous forme radioactive de maniere classique comme l'azidopyridazinyl-gaba 49, soit sous forme non-radioactive comme marqueur d'un recepteur ayant subi des mutations choisies en fonctions de criteres bien particuliers
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22

Langlois, Anaïs. "Rôle du BDNF dans le développement des synapses GABAergiques de l'hippocampe de rat." Thesis, Aix-Marseille, 2012. http://www.theses.fr/2012AIXM4089/document.

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Le cerveau immature est le siège de processus développementaux qui permettent de passer d'une structure primitive à un réseau mature et fonctionnel. L'activité synaptique spontanée générée dans le système nerveux en développement joue un rôle fondamental dans ces processus. Un des principaux moyens par lesquels cette activité peut être traduite en changement phénotypique au niveau neuronal est la sécrétion de neurotrophines. Les neurotrophines sont sécrétées par les neurones et contrôlent toutes les étapes du développement neuronal. Dans l'hippocampe en développement, la neurotrophine principale est le BDNF (brain derived neurotrophic factor). Cette protéine est synthétisée sous forme immature, le proBDNF, dont le rôle est encore méconnu. Durant ma thèse, j'ai montré que le BDNF exerce un contrôle bidirectionnel sur l'efficacité des synapses GABAergiques en développement. La polarité de la plasticité est déterminée par le type d'activité endurée par les neurones et la forme sous laquelle le BDNF est présenté à ces derniers. J'ai ainsi décrit une séquence développementale qui pourrait s'inscrire dans les processus développementaux permettant la maturation du réseau GABAergique dans l'hippocampe de rat<br>The immature brain is the place of developmental processes that allow the switch from a primitive structure to a mature and functional network. Spontaneous synaptic activity generated in the developing nervous system plays a fundamental role in these processes. One of the principal ways this activity is translated into phenotypical changes at the neuronal level is the secretion of neurotrophins. Neurotrophins are secreted by neurons and control each step of neuronal development. In the developing hippocampus, the major neurotrophin is BDNF (brain derived neurotrophic factor). This protein is synthetized under an immature form, proBDNF, which role is still poorly known. During my thesis, I showed that BDNF exerts a bidirectional control on the efficacy of developing GABAergic synapses, which polarity is set by the type of activity endured by neurons and the form of BDNF that is presented to them. I described a developmental sequence which could be a part of the developmental processes allowing the maturation of the GABAergic network in the developing rat hippocampus
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23

Kramer, Vasko [Verfasser]. "Synthese 18 F-markierter Liganden zur Visualisierung der GABA-Bindungsstelle des GABA A-Rezeptors mittels PET / Vasko Kramer." Mainz : Universitätsbibliothek Mainz, 2012. http://d-nb.info/1025406451/34.

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24

Marandi, Nima. "Entwicklungsspezifische Wirkmechanismen der Neurotransmitter GABA und Glyzin." Diss., lmu, 2003. http://nbn-resolving.de/urn:nbn:de:bvb:19-10831.

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25

McGonigle, Ian Vincent. "Molecular pharmacology of an insect GABA receptor." Thesis, University of Cambridge, 2010. https://www.repository.cam.ac.uk/handle/1810/226857.

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Cys-loop receptors are ligand-gated ion channels that are involved in fast synaptic neurotransmission in the central and peripheral nervous system. The Cys-loop receptor RDL ('resistant to dieldrin') is a GABA-gated chloride channel from Drosophila melanogaster and is a major target site for insecticides. The aim of this dissertation was to characterise RDL receptors with particular focus on the agonist binding site. To assess the potency of a range of GABA analogues on RDL receptors, I expressed receptors in Xenopus oocytes and used voltage-clamp electrophysiology to detect receptor responses. I carried out computational modelling of these analogues to determine the dipole separation distances and atomic charges. Computational calculations and functional experiments revealed that agonists require a charged ammonium and an anionic centre, with the most potent agonists having a dipole separation distance of ~5 Å. I made a homology model of the extracellular domain of RDL and docked the active analogues into the putative binding site. I then conducted mutagenesis studies to test the accuracy of this model. Functional data from mutagenesis studies broadly support the location of GABA within this model. This model may be useful for further structure-activity studies and rational drug design. Natural compounds from the traditional Chinese medicine 'Ginkgo biloba' (ginkgolide A, ginkgolide B and bilobalide) have potent insecticidal properties and are similar in structure to picrotoxin. I tested the effect of these compounds on RDL receptor function using voltage-clamp electrophysiology. All compounds were found to inhibit RDL receptor function. I probed the binding site of these compounds using site-directed mutagenesis and electrophysiology. Mutations to the 2'A and 6'T channel-lining (M2) residues greatly reduced the potency of these compounds. I then made a homology model of the transmembrane domain of RDL and docked these compounds into the channel. Compounds docked into the channel pore close to the 2' and 6' channel-lining residues and H-bonding interactions were detected at these locations. Ginkgolides are therefore antagonists of RDL receptors, binding in the channel close to the 2' and 6' residues and this may be the mechanism underlying their potent insecticidal properties. The 5-HT3 receptor is a member of the Cys-loop receptor family and shows homology to RDL receptors. To explore different techniques for studying Cys-loop receptor function I assessed the functionality of two brain derived transcripts of the 5-HT3B subunit (Br1 and Br2) using single-channel electrophysiology and a fluorometric assay. Receptors containing Br1 were found to have a conductance identical to the 5-HT3B subunit whilst Br2 receptors were found not to be expressed. This finding has implications for 5-HT3 brain signalling, in which Br1 may play an important role. In conclusion, work here has described how agonists bind to and activate RDL GABA receptors and I have identified a candidate mechanism for the potent insecticidal properties of Ginkgo biloba extracts. I have also confirmed that 5-HT3 receptor brain transcript Br1 forms functional channels with similar properties to the 5-HT3B subunit.
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26

Jax, Sabine. "Cyclische GABA-Derivate und Nicotinanaloga als Maleinimiden /." München : Hieronymus, 1999. http://www.gbv.de/dms/bs/toc/300875053.pdf.

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27

Alyami, A. M. "Pharmacology of benzodiazepines and GABA in intestine." Thesis, University of Bradford, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.384251.

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28

Taylor, Alison R. "Electrophysiological studies of GABA receptors in insects." Thesis, Open University, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.278439.

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29

Casalotti, S. O. "Molecular characterization of the GABA [A, ] receptor." Thesis, Imperial College London, 1988. http://hdl.handle.net/10044/1/46989.

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30

Bilbe, Graeme. "Molecular studies on the gaba-benzodiazepine receptor." Thesis, Imperial College London, 1985. http://hdl.handle.net/10044/1/37639.

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31

Sudjadi. "Analysis of cloned genes for GABA catabolism." Thesis, University of Leicester, 1991. http://hdl.handle.net/2381/35163.

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A putative hpa+ clone has been isolated allowing an Hpa-Hpc+ mutant CD03 to growth on 4-HPA. Detection of a 4-HPA monooxygenase from extracts was unsuccessful. When it became apparent that gab genes had been cloned the emphasis switched to detailed analysis of those genes. The gab genes were isolated using suppression of a mutant CT101 defective in the sad gene. It seems that the cloned gabDT genes encoding NADP-dependent SSA dehydrogenase and GABA transaminase are responsible for these, not the gabD gene only. Possible explanation of these phenomena are described. E.coli C and K-12 cannot utilise GABA as the sole carbon source. However, E.coli K-12 can mutate to grow on GABA at 30°C but did not at 37°C without further mutation. Both types of mutants were found to have high activities of GABA utilizing enzymes. Studying clones isolated from the wild-type and mutated clones revealed there was a negative regulatory gene, gabR. E.coli K-12 can utilise GABA as the sole nitrogen source at 30°C but not at 37°C. The 1.7 kbp EcoRI-SalI fragment from the wild-type and mutated clones allowed cells to utilise GABA as the sole nitrogen source at 37°C. Thus, the fragment might encode a positive regulatory gene called "gabC". The gene order was determined to be gab"C"DTPR and there were located within the 10.1 kbp EcoRI region. Transcription of gabDTP is from the gabD to gabP direction, whereas gabR appears to be transcribed in the opposite direction. A representation of the organisation and expression of gab genes in E.coli is proposed.
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32

Smith, K. R. "Molecular determinates of GABA-A receptor trafficking." Thesis, University College London (University of London), 2011. http://discovery.ucl.ac.uk/1212232/.

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Gamma amino-butyric acid type A receptors (GABAA receptors) are the main mediators of inhibitory neurotransmission in the CNS. These chloride permeable ligand-gated ion channels are intrinsic to maintaining the excitatory/inhibitory balance of neuronal circuits, a balance that is essential to ensure proper workings of the nervous system. The strength of the inhibitory synapse can be rapidly altered by GABAA receptor trafficking mechanisms, which are tightly regulated by many interacting proteins and post-translational modifications. The identification of GABAA receptor associated proteins is an important tool for deciphering the function of these receptors and how these functions change in pathology. In this study, the interactions of GABAA receptors with three proteins are investigated. First, the results of a yeast-two hybrid screen revealed two novel GABAA receptor β subunit interacting proteins, Maf1 and Macoco. These proteins were shown to be expressed in the hippocampus and cortex and interact with GABAA receptors in brain. Additionally, altering the function of the Maf1/Macoco complex caused changes in GABAA receptor trafficking in neurons. Secondly, the amino acids that mediate the interaction between the GABAA receptor β3 subunit and the clathrin adaptor protein, AP2 were identified. Futhermore, live imaging experiments demonstrated that inhibiting the endocytosis of GABAA receptors by mutating the AP2 binding amino acids can prevent the down-modulation of surface GABAA receptors observed after ischemic insult. Lastly, GABAA receptors were found to interact in a complex with the scaffold and signalling protein GIT1 (GPCR kinase interacting protein). Experiments utilising an RNAi to GIT1 combined with biochemical and confocal microscopy techniques revealed a role for this protein in signalling pathways that regulate GABAA receptor trafficking. This work highlights the importance of GABAA receptor interacting proteins in the regulation of GABAA receptor trafficking and hence inhibitory synapse strength.
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33

Twelvetrees, A. E. "Molecular mechanisms of GABA-A receptor trafficking." Thesis, University College London (University of London), 2010. http://discovery.ucl.ac.uk/815656/.

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Gamma-aminobutyric acid type A receptors (GABA-A receptors) are the main sites of fast synaptic inhibition in the brain. Regulating the numbers of GABA-A receptors at post-synaptic sites is a key mechanism for regulating the strength of inhibitory synaptic transmission. How GABA-A receptors are rapidly transported to synapses is unknown although the trafficking protein huntingtin associated protein 1 (HAP1) is known to regulate surface GABA-A receptor numbers by an uncharacterised mechanism. This study focuses on how HAP1 regulates GABA-A receptor trafficking. This research demonstrates that GABA-A receptors associate with kinesin microtubule motors of the KIF5 family via HAP1, which acts as a kinesin adaptor protein. The interaction of GABA-A receptors with HAP1 and KIF5 is key for the delivery of GABA-A receptors to synapses. Experiments carried out to interfere with the GABA-A receptor/HAP1/KIF5 complex reduced the numbers of GABA-A receptors on the surface of neurons and at synaptic sites. HAP1 is an interaction partner for huntingtin (htt), the protein that when mutated in Huntington’s disease (HD), due to a polyQ expansion in the htt protein, results in toxic functional changes. Htt is shown here to be part of the GABA-A receptor/HAP1/KIF5 trafficking complex and the presence of polyQ-htt reduces GABA-A receptor trafficking, resulting in less GABA-A receptors at synaptic sites. This disrupted GABA-A receptor trafficking may contribute to a molecular explanation of neuronal defects in HD. This work has identified KIF5 dependent transport of GABA-A receptors to synapses as a key mechanism controlling synaptic GABA-A receptor number and the strength of synaptic inhibition under normal conditions, and as a target for pathological disruptions of inhibiton in neurological disease.
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34

Masiulis, Simonas. "Structural studies of human GABA-A receptors." Thesis, University of Oxford, 2017. http://ora.ox.ac.uk/objects/uuid:159d7e7f-3654-45cd-a261-4283100b906d.

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Type-A Î3-amino-butyric acid receptors (GABA<sub>A</sub>Rs) are pentameric ligand-gated ion channels (pLGICs), which mediate the majority of fast inhibitory neurotransmission in the animal central nervous system. Their dysfunction is related to numerous conditions including epilepsy, insomnia, anxiety, panic disorders, depression and schizophrenia. GABA<sub>A</sub>Rs are therefore major targets of clinically important drugs, including benzodiazepines and the intravenous general anaesthetics etomidate and propofol, as well as endogenous modulators, for example neurosteroids. Despite recent progress in structural biology of pLGICs, GABA<sub>A</sub>R structures remain notoriously elusive. Structural information available at the beginning of this project was limited to the benzamidine-bound homopentameric GABA<sub>A</sub>R-Î23, in a desensitised conformation. A large number of fundamental questions, including the molecular architecture of physiological, heteromeric GABA<sub>A</sub>Rs, their signalling mechanisms, the binding and action modes of their numerous ligands, remained to be answered. During this DPhil project, I employed structural biology techniques (X-ray crystallography and single particle cryo-electron microscopy) to further the molecular understanding of human GABAARs. I used subunit-specific llama nanobodies to aid crystallization of homomeric GABA<sub>A</sub>-β3 receptors, which led to a 3.16 Å structure in complex with the general anaesthetic etomidate. This structure elucidates the binding mode of the etomidate, the basis for its subunit selectivity and illustrates conformational changes it triggers. I then used cryo-electron microscopy to determine the first structure of a heteromeric GABA<sub>A</sub>R, the human α1b3g2, bound to an activating llama nanobody at a medium (5.2 Å) resolution. The numerous other insights obtained range from unambiguously establishing the subunit arrangement and stoichiometry, to proposing a mechanism for receptor assembly and discovering an unexpected role played by N-linked glycans in this process. The work described here opens multiple avenues for future research. Immediate opportunities include high resolution structural characterization of heteromeric GABA<sub>A</sub>Rs, via cryo-electron microscopy, further development of nanobodies as novel, high affinity and subunit specific tools to modulate GABA-ergic signalling, and structural characterization of numerous small-molecule modulators, of clinical and physiological relevance, bound to human GABA<sub>A</sub>Rs.
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35

Richter, Grant. "Gaba Drugs For Motor Recovery After Stroke." Thesis, The University of Sydney, 2021. https://hdl.handle.net/2123/25088.

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Clinical reports describe a rare but striking recovery of brain function post stroke after taking the non-benzodiazepine ‘Z-drug’ zolpidem. The underlying mechanism for this is still unknown. This body of work investigates the relationship of Z-drugs and stroke and serves three purposes. Firstly, it furthers our understanding of the particular GABAA receptor subtypes Z-drugs modulate. Benzodiazepines bind between the α-γ2 subunit interfaces (where α is α1, α2, α3, or α5). An analogous binding site is present when γ2 is substituted for γ1 or γ3 but has limited and conflicting pharmacological information. Using concatenated GABAA pentamers expressed in Xenopus laevis oocytes, we observe that zaleplon and eszopiclone modulate γ3 receptors with comparable efficacy potency to γ2, zolpidem does not, and no drug tested modulates γ1 receptors. Supporting this, Z-drug binding within neural tissue was assessed via a competitive autoradiography assay using mice with a γ2F77I mutation that prevents Z-drug binding to the γ2 subunit. This study showed zaleplon and eszopiclone, but not zolpidem displaced flumazenil on γ3 receptors. However, there were no observed differences in zaleplon related neural firing activity measured through c-Fos immunoreactivity. Second, this work explores how stroke may alter the expression levels of benzodiazepine-sensitive GABAA receptors. Because the zolpidem effect is observed months to years after initial injury in humans, we investigated expression three weeks post stroke in mice. The radioligand [3H]-flumazenil's total binding density was assessed via autoradiography. We observed no binding density differences indicating that 3-weeks post-stroke, there are no major increases or decreases in expression levels of benzodiazepine-sensitive GABAA receptors. Finally, this dissertation shows that zolpidem treatment in the late phase of recovery in mice after a photothrombotic cortical stroke does not affect motor recovery speed, highlighting a significant difference between reported observations in the clinic and animal stroke models.
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36

McDonald, Emily F. "Expression of GABA receptors in human sclera." Thesis, Queensland University of Technology, 2014. https://eprints.qut.edu.au/68604/2/Emily_McDonald_Thesis.pdf.

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37

SITAMZE, JEAN-MARIE. "Synthese d'antagonistes du gaba a proprietes ascaricides." Strasbourg 1, 1993. http://www.theses.fr/1993STR15071.

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38

Riffault, Baptiste. "Plasticité GABAergique et épilepsie : focus sur le proBDNF." Thesis, Aix-Marseille, 2016. http://www.theses.fr/2016AIXM4005/document.

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Le facteur neurotrophique dérivé du cerveau (BDNF) synthétisé sous la forme d'un précurseur (proBDNF) qui peut être clivé pour donner sa forme mature (mBDNF). Le mBDNF et le proBDNF produisent des réponses physiologiques opposées par l'activation de deux classes distinctes de récepteurs transmembranaires : respectivement, le récepteur TrkB et p75NTR. Le ratio mature/pro-BDNF est un élément important impliqué dans la plasticité synaptique, la formation des circuits neuronaux et in fine les fonctions cognitives. Les altérations dans ce clivage peuvent ainsi expliquer l’émergence de conditions pathologiques post-lésionnelles, comme la mort cellulaire induite par un état de mal épileptique. Au cours de ma thèse, j'ai montré que l'altération de la maturation du BDNF in vitro, provoquait, via le récepteur p75NTR, une altération de l’activité GABAergique. Par ailleurs, au cours des crises d'épilepsies, les réponses dépolarisantes et excitatrices du GABA, soutenus par la baisse d’expression et d’activité du co-transporteur KCC2, ont été rapportées. Ainsi, in vivo, j’ai montré que la voie proBDNF/p75NTR module l'homéostasie chlore au cours du développement et dans des processus d’épileptogenèse. Pendant le développement, l’activation de la voie proBDNF/p75NTR contrôle le passage d’un GABA immature dépolarisant à un GABA mature hyperpolarisant via KCC2. Pendant l’épileptogenèse, le proBDNF via p75NTR contribuerait à l’hyperexcitabilité des réseaux neuronaux. De plus, le blocage de p75NTR permet de réduire le nombre de crises épileptiques. En conclusion, proBDNF/p75NTR est un facteur clé dans la séquence maturative du GABA et dans la mise en place de l’épilepsie du lobe temporal<br>The brain-derived neurotophic factor (BDNF) is synthesized as a precursor (proBDNF) that can be processed intracellularly to the mature form (mBDNF). mBDNF and proBDNF are assumed to produce opposing physiological responses mediated by the activation of two distinct classes of transmembrane receptors, the TrkB and the p75NTR respectively. The proteolysis of proBDNF is crucial for cognitive functions; its impairment may account for the emergence of brain disorders such as epilepsy. During my thesis, I showed that alteration in BDNF maturation in vitro triggers an up-regulation of p75NTR, inducing a disruption of GABAergic transmission. Moreover, in epilepsy, depolarizing and excitatory GABAergic responses, due to alteration of KCC2, have been reported. Interestingly, I described novel insights into the proBDNF/p75NTR mechanisms and function in vivo in modulating chloride homeostasis during the development of neuronal networks and in the pathogenesis of epilepsy. In physiological conditions, p75NTR activation by proBDNF may be a key regulator in shaping neural circuitry and synaptic plasticity. Moreover, I have shown that proBDNF/p75NTR to mBDNF/TrkB ratio may control the timing of the developmental shift of GABA depolarizing to hyperpolarizing. During epileptogenesis, proBDNF via p75NTR alters the excitatory/inhibitory equilibrium thereby enhancing neuronal activity through the inhibition of KCC2 function. Hence, blockade of p75NTR can prevent some of the epileptogenic mechanisms. Altogether, these data provide the first compelling evidence that proBDNF disrupts the GABA excitatory/inhibitory developmental sequence, which then favors the emergence of epileptic disorders
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39

Engström, Thomas. "GABA-agonister som antipsykotika : En litteraturstudie kring GABA-agonisters potentiella roll som terapeutisk behandling av symptom förekommande vid schizofreni." Thesis, Umeå universitet, Farmakologi, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-137189.

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40

Buckley, Stella Tracey. "GabaA receptor-mediated neurotransmission in human alcoholic brain /." St. Lucia, Qld, 2003. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe17286.pdf.

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41

VANDEVOORDE, VALERIE. "Antagonistes des recepteurs gaba-a : etude structurale et pharmacologique comparative." Strasbourg 1, 1989. http://www.theses.fr/1989STR15070.

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42

Ko, Francoise Dulcinea. "Effect of GABARAP (GABA§A-receptor-associated protein) on the interaction between the dopamine D¦5 and GABA§A receptors." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/MQ58857.pdf.

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43

Glykys, Joseph Charalambos. "GABA[A] receptor subunits mediating tonic inhibition in the hippocampus and the main source of GABA responsible for their activation." Diss., Restricted to subscribing institutions, 2007. http://proquest.umi.com/pqdweb?did=1464110651&sid=1&Fmt=2&clientId=1564&RQT=309&VName=PQD.

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44

Raster, Peter [Verfasser], and Burkhard [Akademischer Betreuer] König. "Synthesis of diarylethenes by cycloaddition & GABA-amides and photoswitchable GABAA-receptor ligands / Peter Raster. Betreuer: Burkhard König." Regensburg : Universitätsbibliothek Regensburg, 2014. http://d-nb.info/1068055804/34.

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45

Höffken, Oliver. "GABA-abhängige Modulation trainingsinduzierter Plastizität im menschlichen Kortex." [S.l.] : [s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=967260124.

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46

Mohamed, Diana. "Kan GABA-transporthämmare fungera som läkemedel mot epilepsi?" Thesis, Linnaeus University, School of Natural Sciences, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:lnu:diva-5694.

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<p>Epilepsi är ingen speciell sjukdom utan ett symtom på en hjärnskada eller störd nervcellsfunktion i hjärnan. Epileptiska anfall beror på abnorm urladdning i hjärnans nervceller. Idag lever omkring 60 000 d.v.s. 0,5-1 % av Sveriges befolkning med epilepsi. Risken att drabbas är störst under det första levnadsåret och efter 65-årsålder då risken att drabbas av stroke är som störst. Behandling av epilepsi används i syfte att hindra uppkomst av anfall och göra det möjligt för den drabbade att leva ett relativt normalt liv. Antiepileptika dämpar aktiviteten i hjärnan och reducerar därmed risken för anfall. Under flera år har man försökt utveckla nya antiepileptika mot andra möjliga targets än de som finns idag, bl.a. GABA-transporthämmare. Det enda förekommande läkemedlet med GABA transporthämmande effekt är tiagabin men detta är inte registrerat som läkemedel i Sverige. Syftet med denna studie var att undersöka om GABA-transporthämmare skulle kunna användas som läkemedel mot epilepsi. Metoden som användes var en litteraturstudie där vetenskapliga artiklar hämtades från PubMed, ELIN, Cochrane och Google Scholar. Arbetet baseras på 4 experimentella originalartiklar och en metaanalys. Artiklarna beskriver antiepileptiska effekter och/eller relaterade egenskaper för olika substanser med hämmande effekter på olika GABA- transportörer. Dessa hämmare, ensamma eller i kombination, visades ge kramplösande effekt i olika djurmodeller av epilepsi. Hämmare av olika GABA-transportörer, till exempel tiagabin och EF1502, gav synergistisk effekt, medan hämmare av samma GABA-transportör, till exempel tiagabin och LU-32-176B, resulterade i additiv effekt. Hämning av olika GABA-transportörer i olika celltyper i och runt synapsklyftan verkar därför kunna ge synergistisk effekt. Ingen synergistisk effekt observerades för toxiska effekter. Det finns anledning att tro att ytterligare läkemedel med effekter på GABA-transportörer kan komma att finnas i framtiden för behandling av epilepsi.</p><br><p>Epilepsy is not a specific disease but a symptom of brain injury or impaired nerve cell function in the brain. Epileptic seizures are symptoms of abnormal activity in the brain neurons. Today, about 60 000 i.e. 0.5-1% of the Swedish population live with epilepsy. The risk of being affected is greatest during the first year of life and after the age of 65 years when the risk for stroke is greatest. The treatment of epilepsy is used in order to prevent the onset of seizures and to allow the patient to live a relatively normal life. Anticonvulsants dampen the activity in the brain and thus reduce the risk of seizures.</p><p>During many years, attempts have been made to develop new anticonvulsants against other potential targets than those that exist today, for example GABA-transporter inhibitors. The only presently used medicine with GABA-transporter inhibiting effect is tiagabine, but this is not licensed as a pharmaceutical drug in Sweden.</p><p>The aim of this study was to investigate whether GABA-transport inhibitors could be used as medication for epilepsy. The method that was used was a literature study in which scientific articles were chosen from PubMed, ELIN, Cochrane and Google Scholar. The work is based on 4 original research articles and one meta-analysis. The articles describe antiepileptic effects and/or related properties of various substances with inhibitory actions on different GABA-transporters. These inhibitors, alone or in combination, were shown to have anticonvulsant effects in several different animal models of epilepsy. Inhibitors of different GABA transporters, such as tiagabine and EF1502, resulted in synergistic effects, while inhibitors of the same GABA transporter, such as tiagabine and LU-32-176 B, resulted in additive effects. Inhibition of various GABA transporters in different cell types in and around synapses therefore seems to provide synergistic effects. No synergistic effect was observed for toxic effects. There is reason to believe that additional drugs with effects on GABA transporters may be used in the future for the treatment of epilepsy.</p>
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47

Olstad, Elisabeth. "Glutamate and GABA: Major Players in Neuronal Metabolism." Doctoral thesis, Norwegian University of Science and Technology, Department of Neuroscience, 2007. http://urn.kb.se/resolve?urn=urn:nbn:no:ntnu:diva-1511.

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<p>Disturbance of neuronal metabolism has implications for a number of neurological and psychiatric conditions, and enhanced knowledge of this is important in developing new methods for treating such disorders. The present research was undertaken to aid understanding of diseases related to disturbance in glutamate and γ-amino butyric acid (GABA) metabolism.</p><p>Two different types of neuronal cell cultures were used in these studies; one containing GABAergic neurons of cerebral neocortical origin and one containing cerebellar neurons. The latter consists primarily of glutamatergic granule neurons in addition to ~6 % GABAergic neurons and a small number of astrocytes. Metabolism was studied by <sup>13</sup>C magnetic resonance spectroscopy (MRS) and mass spectrometry (MS) after adding <sup>13</sup>C-labeled precursors</p><p>([1-<sup>13</sup>C]glucose, [U-13C]glutamate or [U-<sup>13</sup>C]glutamine) to the medium of these cultures. High performance liquid chromatography (HPLC) was used to quantify different amino acids in cell extracts and medium. The amount of protein in the cultures was determined to assess cell damage.</p><p>In the cerebellar neuronal cultures, GABA was present in surprisingly large amounts compared to neocortical GABAergic cultures. <sup>13</sup>C MRS experiments showed that GABA was actively synthesized throughout the culture period by the subpopulation of glutamate decarboxylase (GAD) positive (GABAergic) neurons and subsequently distributed to the other cells in the culture, i.e. to the granule neurons. The function of GABA in these glutamatergic neurons still remains uncertain; however, roles as neurotrophic and neuroprotective agent as well as substrate for energy production have been suggested.</p><p>As shown previously, both glutamate and glutamine were shown to be excellent precursors for intermediary metabolism in cerebellar neurons. However, it was concluded that glutamate was preferred over glutamine, suggesting that these neurons rely more on reuptake of released glutamate than of supply of glutamine from astrocytes for glutamate homeostasis. This is not surprising when considering the cerebellar structure, with few astrocytes compared to neurons and a relatively large distance between astrocyte and synapse.</p><p>Exposure of cerebellar cultures to 50 μM kainic acid (KA), a potent glutamate agonist, which is known to eliminate vesicular release of GABA in these cultures, only marginally affected glutamate and GABA metabolism, whereas increasing the KA concentration to 0.5 mM led to a reduction of both GABA and glutamate metabolism compared to unexposed cultures. It was previously believed that treatment with 50 μM KA eliminated the GABAergic neurons in cerebellar cultures, and KA has therefore been added in order to obtain essentially pure glutamatergic granule cell cultures. Although KA treatment abolishes vesicular GABA release, the GABA synthesizing cells are not eliminated by this treatment and still produce GABA in substantial amounts.</p><p>Results from the present studies can only be understood in terms of inter- and intracellular compartmentation of metabolism. The main focus of metabolic compartmentation studies has been on the two compartments made up by neurons and astrocytes. One pathway previously believed to take place in the astrocytic but not in the neuronal compartment, is the pyruvate recycling pathway for complete tricarboxylic acid (TCA) cycle oxidation of glutamate. Despite this, in one of the present studies, such recycling was clearly present in both astrocytic and neuronal cultures from cerebellum.</p><br>Paper 2 reprinted with kind permission of Elsevier, sciencedirect.com
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48

Jackson, Michael F. "Frequency-dependent actions of GABA enhancing anticonvulsant drugs." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape11/PQDD_0022/NQ50191.pdf.

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49

Cao, Juxiang Locy Robert D. "Functional genomics of GABA metabolism in yeast thermotolerance." Auburn, Ala, 2008. http://repo.lib.auburn.edu/2007%20Fall%20Dissertations/Cao_Juxiang_41.pdf.

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50

Aydar, Ebru. "Pharmacology of GABA and glutamate receptors in insects." Thesis, Oxford Brookes University, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.363779.

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