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University of California Plasticity of Gabaergic Inhibition University of California Los Angeles Plasticity of GABAergic Inhibition A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Molecular, Cellular, and Integrative Physiology by Isabella Ferando 2014 c Copyright by Isabella Ferando 2014 Abstract of the Dissertation Plasticity of GABAergic Inhibition by Isabella Ferando Doctor of Philosophy in Molecular, Cellular, and Integrative Physiology University of California, Los Angeles, 2014 Professor Istvan Mody, Chair γ-aminobtutyric acid (GABA) is a transmitter molecule found in several organs and vir- tually all organisms. In the vertebrate central nervous system it is the major inhibitory neurotransmitter. Here GABA released by GABAergic neurons binds to GABA receptors and regulates neuronal excitability, network synchrony and neuronal development. GABAA − receptors (GABAARs) are highly conserved ligand-gated ion channels permeable to Cl and − HCO3 , and upon binding GABA they generate currents that can be functionally distin- guished in phasic or tonic. Physiology of tonic GABAergic conductances is of particular interest as these exercise powerful constrain on neuronal excitability and gain. Tonic in- hibition is mediated by GABAARs containing δ or α5 subunits localized outside of the synaptic cleft and activated by ambient GABA. Object of this dissertation is plasticity of δ- GABAARs, as their function and distinct pharmacology makes them relevant to many human diseases. δ-GABAARs are naturally insensitive to benzodiazepines while uniquely sensitive to low concentrations of neurosteroids, which act on them as positive allosteric modulators. These endogenous steroids are the neuroactive form of progesterone, cortisol and testos- terone. They are locally synthetized in both neurons and glia and their brain concentration varies in parallel with oscillations in plasma precursors. The present work shows how during times of altered neurosteroid production δ-GABAARs expression homeostatically changes ii with functional consequences on neuronal network functioning. In particular, plasticity of δ-GABAARs during pregnancy and the postpartum affects hippocampal excitability and γ oscillations frequency in vitro. Moreover, over the ovarian cycle, plasticity of δ-GABAARs on interneurons is necessary for fluctuations in γ oscillations amplitude in vivo. More and more evidence suggests an involvement of δ-GABAARs in different kinds of neurological and psychiatric disorders, such as epilepsies, postpartum depression, pre-menstrual dysphoric disorder, and schizophrenia. Interestingly a convenient therapeutic strategy may be avail- able, given the anatomical distribution of these receptors. In fact, δ-GABAARs expressed on excitatory neurons of the cortex contain α4 subunits, whereas on interneurons they contain α1 subunits. This allows to pharmacologically differentiate δ-GABAARs on specific neuron. Development of drugs optimized to selectively modify δ-GABAA-mediated tonic inhibition of excitatory or inhibitory neurons may lead to critical clinical applications. iii The dissertation of Isabella Ferando is approved. Arthur P Arnold Carolyn R Houser Thomas J O'Dell Istvan Mody, Committee Chair University of California, Los Angeles 2014 iv a Giacomo v CONTENTS 1 Introduction1 Bibliography......................................5 2 GABAA receptor modulation by neurosteroids in models of temporal lobe epilepsies 10 2.1 Summary...................................... 11 2.2 Hormones in the Brain............................... 11 2.3 Interneurons, GABAA receptors and Tonic Inhibition.............. 13 2.4 Neurosteroids and Tonic Inhibition........................ 16 2.5 Alterations of Neurosteroid-sensitive GABAAReceptors in an Animal Model of TLE........................................ 18 2.6 References...................................... 20 3 Interneuronal GABAA receptors inside and outside of synapses 24 3.1 Introduction..................................... 25 3.2 GABAARs and tonic/phasic conductances of INs................ 25 3.2.1 Unidentified INs............................... 25 vi 3.2.2 Parvalbumin expressing INs (PV+INs).................. 26 3.2.3 Neurogliaform cells (NGFCs) and Ivy cells (IvyCs)........... 26 3.2.4 Somatostatin expressing INs (SOM+INs)................. 28 3.2.4 Cholecystokinin basket cells (CCK+BCs) and Schaffer collateral-associated INs (SCA-INs).............................. 28 3.3 Conclusions and outlook.............................. 28 3.4 References and recommended reading....................... 28 4 Excitability Changes Related to GABAA Receptor Plasticity during Preg- nancy 32 4.1 Introduction..................................... 33 4.2 Materials and Methods............................... 34 4.3 Results........................................ 35 4.3.1 Changes in δ-GABAAR expression during pregnancy.......... 35 4.3.2 Changes in synaptic I/O function during pregnancy........... 35 4.3.3 Changes in epileptiform network excitability during pregnancy..... 37 4.4 Discussion...................................... 39 4.5 References...................................... 41 5 Altered gamma oscillations during pregnancy through loss of δ subunit- containing GABAA receptors on parvalbumin interneurons 43 5.1 Introduction..................................... 44 5.2 Materials and Methods............................... 45 5.3 Results........................................ 46 5.2.1 PV immunoreactivity remains unchanged in the CA3 at different gesta- tional states................................ 46 5.2.2 CA3 PV+INs express δ-GABAARs.................... 47 vii 5.2.3 surface δ-GABAARs expression decreases during pregnancy in INs of the pyramidal cell layer............................ 47 5.2.4 In vitro CA3 γ oscillation frequency is increased during pregnancy... 49 5.2.5 Increased γ oscillation frequency results from imbalance between activa- tion of NMDA-Rs and δ-GABAARs on INs............... 51 5.2.6 Exposure to ALLO levels found in pregnancy (100 nM) lowers the fre- quency of γ oscillations to pre-pregnancy values............. 52 5.4 Discussion...................................... 52 5.5 Concluding Remarks................................ 55 5.6 References...................................... 55 6 Ovarian cycle-linked plasticity of δ-GABAA receptor subunits in hippocam- pal interneurons affects gamma oscillations in vivo 58 6.1 Summary..................................... 58 6.2 Introduction.................................... 59 6.3 Materials and Methods.............................. 62 6.3.1 Animal Handling............................. 62 6.3.2 Surgery.................................. 62 6.3.3 Ovarian Cycle Induction and Monitoring................ 63 6.3.4 In vivo chronic simultaneous video and local field potential recordings 63 6.3.5 Immunohistochemistry and Microscopy................. 64 6.3.6 Electrophysiology Data Analysis..................... 65 6.3.7 Statistics.................................. 66 6.4 Results....................................... 66 6.4.1 The amplitude of hippocampal γ oscillations recorded in vivo fluctu- ates with phases of the ovarian cycle.................. 66 6.4.2 The amplitude of γ oscillations is constant in WT male and non-cycling female mice................................ 67 viii 6.4.3 The ovarian cycle is associated with δ-GABAAR subunit expression changes in principal cells and interneurons of the hippocampus.... 68 6.4.4 Ovarian cycle-linked fluctuations in γ oscillations amplitudes depend on the presence of δ-GABAARs on PV+INs.............. 69 6.5 Discussion..................................... 71 6.6 Acknowledgments................................. 73 Bibliography...................................... 82 7 In vitro gamma oscillations following partial and complete ablation of δ subunit-containing GABAA receptors from parvalbumin interneurons 90 7.1 Summary..................................... 90 7.2 Introduction.................................... 92 7.3 Materials and Methods.............................. 93 7.3.1 Animal Handling............................. 93 7.3.2 Immunohistochemistry and Microscopy................. 94 7.3.3 Electrophysiology............................. 95 7.3.4 Data Analysis............................... 96 7.4 Results....................................... 96 +=− −=− 7.4.1 Expression of δ-GABAARs in PV-Gabrd and PV-Gabrd mice in PV+INs and PV-INs............................ 96 7.4.2 Frequency of in vitro CA3 γ oscillations following reduction or ablation of δ-GABAARs from PV-INs....................... 98 7.4.3 Differential modulation of γ oscillation frequency by ALLO and DS-2 in slices of PV-Gabrd+=− mice....................... 99 7.5 Discussion..................................... 100 7.6 Acknowledgments................................. 105 Bibliography...................................... 110 ix 8 Conclusions and Future Developments 119 Bibliography...................................... 122 x LIST OF FIGURES 2.1 Schematic representation of two pathways for neurosteroid synthesis and pos- sible differential neurosteroid action on GABAARs............... 13 3.1 Schematic representation of δ-GABAAR-mediated tonic conductances in major subclasses of hippocampal CA1 INs separated by their developmental profile. 27 4.1 Decreased GABAA receptor δ subunit expression in the dentate gyrus in preg- nant animals.................................... 35 4.2 Decreased GABAA receptor δ subunit expression in the striatum in pregnant animals....................................... 36 4.3 No
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