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When Interneurons Get Excited

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When Interneurons Get Excited WHEN INTERNEURONS GET EXCITED - HOW CHANGES IN CHLORIDE CONCENTRATIONS OF PARVALBUMINERGIC INTERNEURONS CAN INFLUENCE BRAIN WORK AND EXCITABILITY Dissertation zur Erlangung des akademischen Grades doctor rerum naturalium (Dr. rer. nat) vorgelegt dem Rat der Medizinischen Fakultät der Friedrich-Schiller-Universität Jena von Diplom-Biologin Melanie Gerth geboren am 04.12.1988 in Altenburg Gutachter: 1. Prof. Dr. med. Christian Hübner, Universitätsklinikum Jena, Institut für Humangenetik 2. Prof. Dr. rer. nat. Aria Baniahmad, Universitätsklinikum Jena , Institut für Human- genetik 3. Prof. Dr. Claudio Rivera Baeza, Institut de Neurobiologie de la Méditerranée, Marseille, Frankreich Tag der öffentlichen Verteidigung: 16.10.2018...... CONTENT List of Abbreviations .................................................................................................................... VII Abstract ........................................................................................................................................ IX Zusammenfassung ........................................................................................................................ X Introduction .................................................................................................................................... 1 Epilepsy ..................................................................................................................................... 1 Interneurons and Inhibition ........................................................................................................ 3 Interneuron subtypes ............................................................................................................. 3 PV+ neurons .......................................................................................................................... 6 GABAergic signalling ................................................................................................................. 9 GABAA receptor (GABAAR) ....................................................................................................... 9 GABAergic inhibition ........................................................................................................... 11 GABAergic excitation .......................................................................................................... 12 Cation-chloride cotransporters (CCCs) ................................................................................... 14 NKCC1 ................................................................................................................................ 14 KCC2 ................................................................................................................................... 18 Preliminary Work ..................................................................................................................... 21 Aim of the study ........................................................................................................................... 23 Material and Methods .................................................................................................................. 24 Mice ......................................................................................................................................... 24 Genotyping .......................................................................................................................... 25 Immunohistochemistry ............................................................................................................ 27 Quantification ...................................................................................................................... 28 Morphology .......................................................................................................................... 31 Corticosterone level ................................................................................................................. 31 Animal handling and blood processing ............................................................................... 31 IV ELISA .................................................................................................................................. 32 Electrophysiology .................................................................................................................... 33 Slice preparation ................................................................................................................. 33 Field potentential recordings ............................................................................................... 33 In vivo experiments ................................................................................................................ 36 Fear conditioning ................................................................................................................. 36 Seizure threshold ................................................................................................................ 37 Statistics .................................................................................................................................. 38 Nomenclature .......................................................................................................................... 39 Results ........................................................................................................................................ 40 General observations .............................................................................................................. 40 Memory and Stress ................................................................................................................. 40 LTP ...................................................................................................................................... 40 Fear conditioning ................................................................................................................. 42 Parvalbuminergic neurons in the superior colliculus ........................................................... 45 Serum corticosterone levels ................................................................................................ 47 Morphology of parvalbuminergic Interneurons ........................................................................ 48 Loss of PV+ interneurons ......................................................................................................... 49 Excitability ............................................................................................................................... 54 EPSP – to – Spike coupling ................................................................................................. 54 Seizure susceptibility ........................................................................................................... 56 Discussion ................................................................................................................................... 58 Phenotypical characterisation ................................................................................................. 58 Electrophysiological characterisation ...................................................................................... 66 Epilepsy ................................................................................................................................... 74 Conclusion and Outlook .............................................................................................................. 80 References .................................................................................................................................. 82 V Appendix ................................................................................................................................... 107 List of gene names figure 1 ............................................................................................... 107 Result tables Fear conditioning ......................................................................................... 109 Ehrenwörtliche Erklärung .......................................................................................................... 111 Danksagung .............................................................................................................................. 112 VI LIST OF ABBREVIATIONS 5HT3aR 5-hydroxytryptamine GABA gamma-aminobutyric (serotonin) receptor acid ACTH adrenocorticotropic GABAR gamma-aminobutyric hormone acid receptor AIS axon initial segment HFS high frequency stimulus ALS amyotrophic lateral HPA axis hypothalamic pituitary sclerosis adrenal axis BLA basolateral amygdaloid I current nucleus IHC immunohistochemistry CBP calcium-binding protein IPSC inhibitory postsynaptic CCC cation-chloride current cotransporter IPSP inhibitory postsynaptic CeA central nucleus of potential amygdala KCC2 potassium-chloride CNS central nervous system cotransporter 2 CORT corticosterone KCC3 potassium-chloride cotransporter 3 CRH corticotropin-releasing hormone KO knock out Ctx cortex LTP long term potentiation EPSP excitatory postsynaptic NKCC1 sodium-potassium- potential chloride cotransporter 1 fEPSP field EPSP OLM cells oriens-lacunosum moleculare neurons VII PBGN parabigeminal nucleus PPR paired pulse ratio PTZ pentylenetetrazole PV parvalbumin PVN paraventricular nucleus R resistance SC superior colliculus SLC12 soluble
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