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The Transcriptomic Profile and Synaptic Excitability of Vasoactive Intestinal Peptide-Expressing Interneurons in the Mouse Hippocampus

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The transcriptomic profile and synaptic excitability of vasoactive intestinal peptide-expressing interneurons in the mouse hippocampus Thèse Xiao Luo Doctorat en biochimie Philosophiæ doctor (Ph. D.) Québec, Canada © Xiao Luo, 2018 The transcriptomic profile and synaptic excitability of vasoactive intestinal peptide-expressing interneurons in the mouse hippocampus Thèse Xiao Luo Sous la direction de : Lisa Topolnik, directeur de recherche Résumé Les neurones sont les éléments constitutifs du système nerveux. Dans le cortex, les neurones peuvent être divisés en cellules principales qui effectuent des calculs excitateurs via des connexions synaptiques locales et à longue distance et des interneurones qui contrôlent tous les domaines subcellulaires des cellules principales. Les interneurones inhibent les cellules principales en hyperpolarisant la membrane postsynaptique via les récepteurs GABA. En plus de contrôler le niveau d’excitabilité de cellules isolées via une inhibition transitoire ou à long terme, elles coordonnent le déclenchement des ensembles cellulaires principaux pour générer des oscillations de réseau qui traversent les zones du cerveau. Le dysfonctionnement des interneurones entraîne des troubles cérébraux comme la schizophrénie, l'autisme et l'épilepsie. Contrairement aux cellules principales, les interneurones présentent un haut niveau de diversité, cohérent avec leurs différents rôles fonctionnels dans les circuits cérébraux. Pour comprendre leurs fonctions de réseau, les neuroscientifiques ont développé plusieurs critères pour classer les interneurones, notamment la cytomorphologie, la connectivité, les propriétés électrophysiologiques et les marqueurs moléculaires. En général, trois types d’interneurones représentent la majorité des interneurones corticaux: les cellules somatostatine (SOM)+ ciblant la dendrite, les cellules parvalbumine (PV)+ ciblant le soma, et les cellules l'interneurone specifique peptide vasoactif intestinal (VIP)+. Dans l'hippocampe, les cellules VIP+ (hormis les cellules VIP+) jouent un rôle unique dans le réseau, car elles innervent de préférence les interneurones mais évitent les cellules principales. Cependant, leur taxonomie et leurs propriétés physiologiques sont moins claires que celles des autres types d’interneurones. Mon projet de thèse a porté sur deux sous-types de cellules VIP: la cellule VIP+ à cellule longue et la cellule à interneurone de type 3 (IS3). Une nouvelle cellule VIP+ à longue projection (VIP-LRP) a été identifiée dans l'hippocampe CA1 Oriens/Alveus (Francavilla et al., 2018). Ces cellules ciblent de manière sélective les interneurones dans la zone hippocampique CA1, mais se projettent également dans le subiculum de la zone voisine. En outre, ils sont plus actifs pendant la période stationnaire d'éveil et silencieux pendant les oscillations thêta ou d'ondulation. Cependant, les marqueurs moléculaires qu'ils expriment n'étaient pas clairs. Pour examiner leurs marqueurs moléculaires et développer des lignées de souris spécifiques de type cellulaire en utilisant une approche génétique combinatoire, j'ai d'abord procédé à une immunohistochimie pour déterminer les marqueurs couramment exprimés, notamment le récepteur muscarinique 2, la cholécystokinine, la calbidine nNOS), calrétinine (CR) et SOM dans les cellules VIP dans les striatum oriens (SO) de CA1. Nous avons constaté que les cellules VIP-LRP étaient négatives pour SOM et nNOS, mais que la moitié d'entre elles exprimaient M2R. De plus, une petite fraction des cellules GFP expriment CCK, CB et CR. La proportion de cellules M2R + VIP-LRP était différente entre différentes souches de souris. Ensuite, nous avons effectué le profilage transcriptomique de VIP-LRP identifiés anatomiquement en utilisant le séquençage d'ARN à cellule unique. J'ai identifié plusieurs iii marqueurs moléculaires, tels que la proenképhaline, le neuropeptide Y et la nétrine G1, ainsi que de nombreux autres gènes appartenant à plusieurs familles de gènes importantes: canaux ioniques, récepteurs de neurotransmetteurs, neuromodulateurs, molécules d'adhésion cellulaire et de myélinisation. De plus, les LRP VIP partagent des gènes communs lors de la comparaison avec les types de cellules VIP, CR et VIP, CCK dans le néocortex. Ensemble, ces données suggèrent que même si les LRP-VIP représentent un groupe intermédiaire dans le sous-type VIP, ils peuvent exprimer des gènes liés à des caractéristiques spécifiques permettant une coordination à longue distance des activités neuronales dans le CA1 et le subiculum. Après cela, j'ai examiné les propriétés synaptiques excitatrices d'un autre sous-type VIP +, la cellule IS3. Des études antérieures ont montré qu’ils fabriquaient des synapses sur les interneurones dans le SO, qui contrôlent à leur tour l’intégration des apports excitateurs reçus par les dendrites proximales et distales des cellules pyramidales. Cependant, les propriétés des entrées excitatrices véhiculant les cellules IS3 restent inconnues. En utilisant l'enregistrement par patch clamp et le recalage du glutamate à deux photons, nous avons évalué les propriétés synaptiques de deux entrées excitatrices formées sur les cellules IS3 par les collatérales de Schaffer (CA) et la voie temporoammonique (TA) du cortex entorhinal. Les résultats ont montré que les courants postsynaptiques excitateurs (EPSC) évoqués dans les cellules IS3 par stimulation électrique de la voie TA avaient une amplitude, une élévation et un temps de décroissance inférieurs à ceux des synapses SC. De plus, la transmission synaptique TA-IS3 était médiée par les récepteurs AMPA et NMDA. En outre, les deux AT et SC- EPSC ont montré une facilitation synaptique à court terme en réponse à une stimulation répétitive. Enfin, les voies TA et SC ont montré un degré similaire d'intégration spatiale. Lorsque ces propriétés synaptiques ont été incorporées dans le modèle de calcul IS3 in vivo (Guet-McCreight et al., 2016), l'activation des cellules IS3 peut être provoquée par ces entrées excitatrices au cours des oscillations du thêta et de l'ondulation hippocampique. L'imagerie in vivo à deux photons chez des souris éveillées a montré que le déclenchement des cellules IS3 augmentait pendant le rythme thêta, alors que leurs activités n'étaient pas associées iv Summary Neurons are the building blocks of nervous system. In the cortex, neurons can be divided into principal cells that perform excitatory computations through local and long-range synaptic connections and interneurons that controls all subcellular domains of principal cells. Interneurons inhibit principal cells by hyperpolarizing the postsynaptic membrane via GABA receptors. In addition to controlling the level of excitability of single cells via transient or long-lasting inhibition, they coordinate the firing of principal cell ensembles to generate network oscillations that travel across brain areas. The malfunction of interneurons leads to severe brain disorders such as schizophrenia, autism and epilepsy. In contrast to principal cells, interneurons display high level of diversity, consistant with their various functional roles in the brain circuitry. To understand their network functions, neuroscientists have developed several criteria to classify interneurons, including cytomorphology, connectivity, electrophysiological properties, and molecular markers. In general, three interneuron types account for the majority of cortical interneurons: dendrite- targeting somatostatin (SOM)+ cells, soma-targeting parvalbumin (PV)+ cells, and interneuron-specific vasoactive intestinal peptide (VIP)+ cells. In the hippocampus, VIP+ cells (excluding VIP+ basket cell) play a unique role in the network, since they preferentially innervate interneurons but avoid principal cells. However, their taxonomy and physiological properties are less clear compared to other interneuron types. My PhD project focused on two subtype of VIP cells: VIP+ long-projecting cell and type 3 interneuron-specific (IS3) cell. A novel long-projecting VIP+ cell (VIP-LRP) has been identified in the hippocampal CA1 Oriens/Alveus (Francavilla et al., 2018). These cells selectively target interneurons in the hippocampal CA1 area, but also project to the neighbouring area subiculum. In addition, they are more active during the stationary period of wakefulness, and silent during theta or ripple oscillations. However, the molecular markers they express were unclear. To examine their molecular markers and develop cell-type specific mouse lines using combinatorial genetic approach, I first performed immunohistochemistry to profile commonly expressed markers including muscarinic receptor 2 (M2R), cholecystokinin (CCK), calbidin (CB), neuronal nitric oxide synthase (nNOS), calretinin (CR), and SOM in VIP cells in the striatum oriens (SO) of CA1. We found that VIP-LRP cells were negative for SOM and nNOS but half of them expressed M2R. Moreover, a small fraction of GFP cells express CCK, CB, and CR. The proportion of M2R+ VIP-LRP cells was different between different mouse strains. Next, we performed transcriptomic profiling of anatomically identified VIP-LRPs using single-cell RNA sequencing. I identified several molecular markers, such as proenkephalin, neuropeptide Y and netrin G1, as well as many other genes that belong to several important gene families including ion channels, neurotransmitter receptors, neuromodulators, cell adhesion and myelination molecules. In addition, VIP-LRPs share common genes when comparing with VIP;CR and VIP;CCK cell types in the neocortex.
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