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Characterization of Calcium Signals Generated by Activation of the Two Excitatory Synaptic Inputs in Purkinje Neurons Karima Ait Ouares

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Characterization of Calcium Signals Generated by Activation of the Two Excitatory Synaptic Inputs in Purkinje Neurons Karima Ait Ouares Characterization of calcium signals generated by activation of the two excitatory synaptic inputs in Purkinje neurons Karima Ait Ouares To cite this version: Karima Ait Ouares. Characterization of calcium signals generated by activation of the two excitatory synaptic inputs in Purkinje neurons. Biomechanics [physics.med-ph]. Université Grenoble Alpes, 2019. English. NNT : 2019GREAY014. tel-02887099 HAL Id: tel-02887099 https://tel.archives-ouvertes.fr/tel-02887099 Submitted on 2 Jul 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. THÈSE Pour obtenir le grade de DOCTEUR DE LA COMMUNAUTE UNIVERSITE GRENOBLE ALPES Spécialité : Physique pour les sciences du vivant Arrêté ministériel : 25 mai 2016 Présentée par Karima AIT OUARES Thèse dirigée par Marco CANEPARI, CR Inserm, Université Grenoble Alpes et CNRS UMR 5588 Préparée au sein du Laboratoire Interdisciplinaire de Physique dans l'École Doctorale de Physique de Grenoble Caractérisation des signaux calciques générés par l’activation des deux voies synaptiques excitatrices des neurones de Purkinje Thèse soutenue publiquement le 11 Avril 2019 , devant le jury composé de : Mr Boris, BARBOUR DR CNRS – ENS Paris, Rapporteur Mr Philippe, LORY DR CNRS – IGF Montpellier, Rapporteur Mme, Micaela, GALANTE MC – Université Paris Sud, Membre Mme, Cécile, DELACOUR CR CNRS – Institut Néel Grenoble, Membre Mr, Claude, VERDIER DR CNRS – LIPhy Grenoble, Président Acknowledgements I would like to express my immense gratitude to all those who have made this thesis possible. Firstly, I would like to thank my supervisor Marco Canepari for giving me the opportunity to further my academic career. Thank you for your infinite patience and confidence. I would like to thank “MOTIV” team for welcoming me and for allowing me to be part of the team. Finally, I owe my deepest gratitude to my family and my friends. There are no words that can describe all the support that you have given me. 2 Contents Acknowledgements ……………………………………………………………………………………….. 02 Contents……………………………………………………………………………………………………. 03 Abstract (English)………………………………………………………………………………………….. 07 Abstract (French)…………………………………………………………………………………………...09 ------------------------------------------------------------Chapter 1---------------------------------------------------------- Introduction 1.1 The cerebellum, its anatomy and its circuitry 1.1.1 Brief overview on historical studies of the cerebellum……………………………… 12 1.1.2 The anatomy of the cerebellum……………………………………………………….. 16 1.1.3 The layers of the cerebellar cortex……………………………………………………. 18 1.1.4 The functional organization of the cerebellum………………………………………. 21 1.1.5 The excitatory circuitry of the cerebellar cortex……………………………………... 23 1.1.6 Purkinje neurons……………………………………………………………………….. 26 1.2 Properties of Purkinje neurons 1.2.1 Passive properties of Purkinje neurons……………………………………………… 28 1.2.2 Active properties in the soma and axon of Purkinje neurons……………………... 30 1.2.3 Active properties of Purkinje neuron dendrites………………………………........... 34 1.3 Ion channels of cerebellar Purkinje neurons 1.3.1 Fundamentals of Voltage Gated Calcium channels (VGCCs)…………………….. 35 1.3.2 HVA-VGCCs in Purkinje neuron dendrites…………………………………………... 37 1.3.3 LVA-VGCCs in Purkinje neuron dendrites…………………………………………… 39 1.3.4 Voltage-activated K+ channels in Purkinje neuron dendrites……………………… 40 1.3.5 Ca2+ activated K+ channels in Purkinje neuron dendrites………………………….. 42 1.4 Synaptic signaling by mGuR1 in Purkinje neurons 1.4.1 Type-1 metabotropic glutamate receptors………………………………………….... 47 1.4.2 mGluR1 in Purkinje neurons…………………………………………………………... 49 1.4.3 Specificity of mGluR signaling at PF-PN synapse………………………………….. 51 1.5 Open questions that motivated my experiments………………………………………………… 54 3 Contents ------------------------------------------------------------Chapter 2----------------------------------------------------------- Material and methods 2.1 Mice and ethics for animal experimentation........................................................................... 56 2.2 Slice preparation…………………………………………………………………………………… 56 2.3 Electrophysiology………………………………………………………………………………….. 57 2.4 Neuronal loading and staining.............................................................................................. 59 2.5 The imaging system............................................................................................................... 60 2.6 Fluorescent indicators……………………………………………………………………………… 63 2.7 Membrane potential calibration and signals interpretation..................................................... 63 2.8 Pharmacology....................................................................................................................... 65 2.9 Optical data analysis……………………………………………………………………………….. 66 2.10 Statistics……………………………………………………………………………………………... 66 ------------------------------------------------------------Chapter 3----------------------------------------------------------- Dendritic Ca2+ and K+ channels activated by the CF-EPSP in PN neurons 3.1 Dendritic depolarization and Ca2+ transients associated with the CF-EPSP…………………. 72 3.2 Dendritic VGCC channels activated during CF-EPSP at different initial Vm state…………… 78 3.3 Dendritic Ca2+- activated K+ channels activated by the CF-EPSP…………………………….. 87 3.4 Dendritic A-type VGKC activation by the CF-EPSP…………………………………………….. 91 3.5 Conclusions………………………………………………………………………………………….. 95 ------------------------------------------------------------Chapter 4----------------------------------------------------------- Dendritic supralinear Ca2+ signal underlying concomitant PF and CF activity 4.1 Dendritic Ca2+ signals associated with pairing PF-CF stimulation……………………………... 98 4.2 mGluR1 contribution to the supralinear Ca2+ signals associated with paring PF-CF stimulation……………………………………………………………………………………………. 102 4 Contents 4.3 Physiological mGluR1-dependant supralinear Ca2+ signals are not due to A-type K+ channels inactivation and P/Q-type channels activation…………………………………………………… 106 4.3.1 The effect of direct chemical stimulation of mGluR1s on the Ca2+ signal associated with the CF-EPSP ………………………………………………………………………….106 2+ 4.3.2 Combined imaging of Vm and Ca signals associated with PF-CF paired stimulation…………………………………………………………………………………...110 4.4 Physiological mGluR1-dependant supralinear Ca2+ signals are not due to the transient saturation of endogenous Ca2+ buffers…………………………………………………………… 114 2+ 2+ 4.5 Physiological mGluR1-dependant supralinear Ca signals are not due to InsP3-mediated Ca release from stores………………………………………………………………………………….. 119 4.6 The slow mGluR1-activated cation conductance is correlated with the physiological mGluR1- dependant supralinear Ca2+ transient…………………………………………………………….. 122 4.7 Conclusions………………………………………………………………………………………….. 126 ------------------------------------------------------------Chapter 5----------------------------------------------------------- Discussion 5.1 Discussion of results in Chapter 3………………………………………………………………… 129 5.2 Discussion of results in Chapter 4………………………………………………………………… 135 5.3 Future perspectives…………………………………………………………………………………. 141 References………………………………………………………………………………………………… 142 Annex……………………………………………………………………………………………………….. 171 5 Abstract Abstract (English) In the cerebellum, the interplay between PFs and CF inputs generates supralinear Ca2+ signals that provide the information on their concomitant occurrence. These phenomena trigger both short- and long-term depression at PF- PN synapses associated with motor learning and coordination, i.e. the primary functions of the cerebellum. While activation of PFs elicits local Ca2+ transients that are confined to activated spines, the activation of the CF generates a large depolarization that spreads passively into the dendrites. The CF-mediated transient dendritic depolarization, not localized, plays a fundamental role in dendritic integration and in regulating local PF signals and their plasticity at distal sites. The study carried out in my thesis addressed two crucial questions of this problem: the dendritic ion channels activated by the CF-mediated dendritic depolarization at 2+ different initial Vm and the mechanisms underlying dendritic supralinear Ca signals associated with concomitant PF and CF activity. The results reported here were 2+ obtained using recent optical methods of Vm imaging and ultrafast Ca imaging with low affinity Ca2+ and high affinity Ca2+ indicators combined with pharmacological analysis. During the first part of my work, I characterized the behavior of the dendritic 2+ + Ca and K channels activated by CF-EPSPs at different initial dendritic Vm, using 2+ optical measurements of Vm and Ca transients. We found that two different sets of ion channels are selectively activated at different states. When the dendrite is hyperpolarized, CF-EPSPs mainly activate T-type voltage-gated Ca2+ channels (VGCCs), SK channels and A-type voltage-gated Ca2+ channels (VGKCs) that limit the transient Vm below ~0 mV. When in contrast the dendrite is depolarized,
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