Huntington’s disease (HD) is a progressive neurodegenerative disorder caused by an aberrant expansion of CAG repeats within the HTT gene, for which there is currently no cure. The disease is driven by the mutant huntingtin protein, which predominantly leads to the degeneration of the striatum within the brain. Medium-sized spiny neurons (MSNs), the main neuronal components of the striatum, are selectively affected by HD, and they can be further categorized by their surface expression of Dopamine receptors 1 (D1R) and 2 (D2R). These two populations exhibit distinct vulnerabilities, with D2R-expressing MSNs impacted earlier in the disease process, though the reasons for this differential susceptibility remain unclear. Understanding the mechanisms underlying the specific vulnerability of D2R-MSNs, or the resilience of D1R-MSNs, could guide strategies to delay neurodegeneration. In this study, we utilized an HD knock-in mouse model carrying 18 (HttQ20, “control”) or approximately 190 (HttQ175, “HD”) CAG repeats. This model also expresses tdTomato and EGFP fluorescent proteins under the control of Drd1 and Drd2 promoters, respectively, enabling visualization and differentiation of MSNs. Using this model, we conducted a multidimensional analysis to identify features that contribute to MSNs vulnerability. Transcriptomic analysis of small pools of MSNs collected from 8-week-old, presymptomatic mice revealed an overall downregulation of retrotransposable elements in both neuronal classes in the HD group. Notably, in D1R-MSNs, pathways related to oxidative phosphorylation and translation were upregulated in HD mice, suggesting a potential compensatory mechanism that might prevent from mutant huntingtin aggregation. Consistently, we observed an early increase in huntingtin aggregates in D2R-MSNs compared to D1R-MSNs. Furthermore, D2R-MSNs showed greater sensitivity to CAG somatic instability, potentially contributing to their earlier susceptibility to HD. While HD central nervous system symptoms are well-documented, the ubiquitous expression of mutant huntingtin results in a range of peripheral symptoms, including gastrointestinal (GI) disturbances. These symptoms, which appear as early as the prodromal phase, contribute significantly to patient isolation and reduced quality of life. Although some studies have reported alterations in the enteric nervous system (ENS) of HD patients, including mutant huntingtin aggregation, little research has explored this characteristic in-depth. Using the HttQ175 mouse model, we investigated whether ENS and GI alterations observed in patients could be modelled and characterized. To this aim, we successfully established a number of protocols to isolate and visualize ENS ganglia and GI structures, and to culture enteric primary cells. Then, preliminary studies seemed to suggest morphological abnormalities and elevated expression of pro-inflammatory markers such as S100b and IL-6 in HD enteric cultures. In vivo experiments revealed increased expression of specific Bdnf isoforms at presymptomatic stages, and elevated levels of the 55 kDa Gfap protein isoform in symptomatic-stage colonic tissue. While these molecular changes were not conclusively linked to functional or gross structural GI tract alterations, these preliminary findings further support the need to explore GI molecular, cellular and functional alteration in HD, with potential implications for therapeutic development to enhancing patient quality of life. Overall, this thesis offers valuable insights into the cellular and molecular mechanisms of HD, spanning central and peripheral nervous system effects, and contributes to the identification of novel biomarkers, potentially paving the way for improved diagnostic and therapeutic strategies.

D’après le postulat de Hebb, les circuits neuronaux ajustent et modifient durablement leurs poids synaptiques en fonction des patrons de décharges de part et d’autre de la synapse. La « spike-timing-dependent plasticity » (STDP) est une règle d’apprentissage synaptique hebbienne dépendante de la séquence temporelle précise (de l’ordre de la milliseconde) des activités appariées des neurones pré- et post-synaptiques. Le striatum, le principal noyau d’entrée des ganglions de la base, reçoit des afférences excitatrices provenant du cortex cérébral et du thalamus dont les activités peuvent être concomitantes ou décalées dans le temps. Ainsi, l’encodage temporal des informations corticales et thalamiques via la STDP pourrait être crucial pour l’implication du striatum dans l’apprentissage procédural. Nous avons exploré les plasticités synaptiques cortico- et thalamo-striatales puis leurs interactions à travers le paradigme de la STDP. Les principaux résultats sont :1. Les « spike-timing-dependent plasticity » opposées cortico-striatales et thalamo-striatales induisent des plasticités hétérosynaptiques. Si la très grande majorité des études sont consacrées à la plasticité synaptique cortico-striatale, peu ont exploré les règles de plasticité synaptique aux synapses thalamo-striatale et leurs interactions avec la plasticité cortico-striatale. Nous avons étudié la STDP thalamo-striatale et comment les plasticités synaptiques thalamo- et cortico-striatales interagissent… / According to Hebbian postulate, neural circuits tune their synaptic weights depending on patterned firing of action potential on either side of the synapse. Spike-timing-dependent plasticity (STDP) is an experimental implementation of Hebbian plasticity that relies on the precise order and the millisecond timing of the paired activities in pre- and postsynaptic neurons. The striatum, the primary entrance to basal ganglia, integrates excitatory inputs from both cerebral cortex and thalamus whose activities can be concomitant or delayed. Thus, temporal coding of cortical and thalamic information via STDP paradigm may be crucial for the role of the striatum in procedural learning. Here, we explored cortico-striatal and thalamo-striatal synaptic plasticity and their interplay through STDP paradigm. The main results described here are:1. Opposing spike-timing dependent plasticity at cortical and thalamic inputs drive heterosynaptic plasticity in striatumIf the vast majority of the studies focused on cortico-striatal synaptic plasticity, much less is known about thalamo-striatal plasticity rules and their interplay with cortico-striatal plasticity. Here, we explored thalamo-striatal STDP and how thalamo-striatal and cortico-striatal synaptic plasticity interplay. a) While bidirectional and anti-Hebbian STDP was observed at cortico-striatal synapses, thalamo-striatal exhibited bidirectional and hebbian STDP...