Membres de l'équipe

JG
OV
sylviane-lortet-square
AN
TR
PK

Interactions cellulaires, neurodégénérescence et neuroplasticité

Nous étudions l'organisation et la dynamique fonctionnelle des circuits neuronaux du cerveau, leurs capacités d'adaptation et les mécanismes qui sous-tendent leur dysfonctionnement pathologique et leur neurodégénérescence, avec un focus sur le réseau des ganglions de la base.

Notre principal intérêt de recherche porte sur la transmission synaptique, la neurodégénération et la neuroplasticité dans le cerveau adulte. La communication entre les neurones au niveau de leurs connexions, appelées synapses, est le substrat du traitement de l’information dans les réseaux qui sous-tendent les fonctions cérébrales. La transmission synaptique est un processus hautement dynamique et régulé, influencé par les cellules gliales, dont les anomalies sont associées à un certain nombre de maladies cérébrales (notion de synaptopathies). Neurodégénérescence est un processus pathologique qui déclenche le dysfonctionnement et la mort progressive des cellules nerveuses. La compréhension des mécanismes pathologiques qui déclenchent et entretiennent la neurodégénérescence (pathogenèse), de ses conséquences sur le fonctionnement des circuits et des mécanismes qui aident les neurones à gérer le stress cellulaire est essentielle pour le développement de traitements curatifs ou modificateurs de la maladie pour les troubles neurodégénératifs dévastateurs, tels que la maladie de Parkinson (MP). Neuroplasticité. désigne la capacité du système nerveux à s’adapter en réponse à l’expérience et aux stimulations internes ou externes en modifiant les interactions entre les cellules nerveuses, y compris les changements dans le nombre de synapses et l’efficacité/la force de la transmission synaptique (plasticité synaptique), ou en générant de nouvelles cellules nerveuses. Cette faculté n’est pas limitée au développement, mais se produit tout au long de la vie, bien qu’elle diminue avec le vieillissement. La neuroplasticité a notamment été impliquée dans les processus d’apprentissage et de mémoire. Elle se produit également dans des conditions pathologiques ou en réponse à des traitements chroniques. Ces changements adaptatifs peuvent représenter des mécanismes compensatoires contrecarrant les déficits déclenchés par le dysfonctionnement ou la mort neuronale, retardant l’apparition des symptômes, ou, au contraire, participer à ces déficits, voire les aggraver.

L’équipe étudie ces processus dans le contexte des fonctions et des pathologies liées aux ganglions de la base (BG), en particulier la MP, un trouble du mouvement caractérisé par la dégénérescence des neurones dopaminergiques du mésencéphale innervant le striatum, la principale station d’entrée des BG. Par le biais de collaborations, nos travaux abordent également des questions fondamentales et cliniquement pertinentes dans le contexte d’autres neuropathologies, notamment les troubles du spectre autistique (TSA), la maladie d’Alzheimer et la maladie de Charcot-Marie-Tooth.

Vue de type coloration de Golgi d'un neurone épineux striatal de taille moyenne obtenue par traçage rétrograde viral, qui révèle ses arborisations dendritiques fines et sa forte densité d'épines qui sont les sièges post-synaptiques primaires des connexions excitatrices.

Publications

Nos dernières publications

Actualités

de l'équipe

Membres de l'équipe

Ils dirigent nos recherches

Alumni

Ils ont contribué à nos activités
Maxime Assous
Associé de recherche, Centre de neurosciences moléculaires et comportementales, Université Rutger, Newark, NJ, USA.
Abid Oueslati
Professeur associé (Département de médecine moléculaire, Université Laval), directeur du Laboratoire de neurodégénération moléculaire et cellulaire, Centre de recherche du CHU, Québec, Canada.

Les organismes qui nous financent

Ils soutiennent nos recherches
ARN
Fondation Alzheimer
Fondation de France

Galerie

Interactions cellulaires, neurodégénérescence et neuroplasticité

The team investigates synaptic transmission, neurodegeneration and neuroplasticity in the context of BG-related functions and pathologies, with a focus on PD. Our approach combines the use and development of relevant experimental models in rodents (chronic deep brain stimulation, cell specific ablation, optogenetic or chemogenetic modulation of neuronal activity) with a variety of analytic tools, including behavioral tests, functional anatomy, tract-tracing and electrophysiology and is implemented with genetics, imaging and molecular biology in drosophila models. Ongoing research lines have two main objectives:

1. Gain knowledge on the anatomofunctional organization of the BG network and its remodeling in pathological condition, which may help design novel symptomatic treatments.

Our current work is centered on striatal cholinergic interneurons (CINs) and on corticostriatal synaptic function/plasticity in two pathological conditions: PD and ASD.

Regarding PD, we previously provided evidence for a causal role of CINs in parkinsonian symptomatology by showing that their optogenetic inhibition alleviates PD-like motor deficits (Maurice et al., 2015; Ztaou et al., 2016). Ongoing work aims at providing mechanistic insights into the antiparkinsonian potential of targeting these interneurons. We are challenging the hypothesis that abnormalities in CINs signaling contribute to altered corticostriatal transmission and plasticity in PD state, and that this implication depends on the thalamostriatal information they integrate. Our most recent data show that inhibiting CINs potentiates corticostriatal transmission in D1 receptor-expressing projection neurons, partially restores plasticity at corticostriatal synapses and alleviates motor-skill learning deficits in a mouse model of PD (Laverne et al., 2022).

Regarding ASD, we are pursuing a collaborative work with the team of Laurent Fasano at the IBDM that associated heterozygous deletion of TSHZ/Tshz3 with ASD (Caubit et al., 2016), a neurodevelopmental disorder defined by social interaction deficits and repetitive behaviors. The characterization of mouse models of conditional Tshz3 deletion from cell to behavior further showed that TSHZ3 plays a crucial postnatal role in the functioning of the corticostriatal circuitry (Chabbert et al., 2019; Caubit et al., 2021), and that dysfunction in cortical projection neurons or in CINs segregates with distinct core features of ASD, respectively social interaction deficits and repetitive/stereotyped behavior (Caubit et al., 2022). Ongoing work aims at deciphering the mechanisms of CIN dysfunction, its consequences on the functioning of the corticostriatal circuit, as well as the links with the striosome/matrix organization of the striatum and stereotyped behaviors.
Double labeling, in the striatum of transgenic mice, of the striatal output neurons expressing the dopamine D1 receptor (red fluorescence) and the cholinergic interneurons (green fluorescence) in which halorhodopsin expression allows their photo-inhibition. The electrophysiological trace illustrates the interruption of the spontaneous spiking of one recorded cholinergic interneuron when amber light is delivered in vivo into the striatum.Ⓒ Nicolas Maurice, IBDM, Marseille.
Double labeling, in the striatum of transgenic mice, of the striatal output neurons expressing the dopamine D1 receptor (red fluorescence) and the cholinergic interneurons (green fluorescence) in which halorhodopsin expression allows their photo-inhibition. The electrophysiological trace illustrates the interruption of the spontaneous spiking of one recorded cholinergic interneuron when amber light is delivered in vivo into the striatum.Ⓒ Nicolas Maurice, IBDM, Marseille.

2. Identify players in neuron death or defense pathways against cellular stress that may represent new targets for disease-modifying strategies.

This research is performed in the context of PD, but also of Alzheimer’s disease and Charcot-Marie-Tooth disease.

A first part is centered on the mechanisms regulating autophagy, mitochondrial dynamics and mitochondrial quality control via mitophagy, which are main players in neurodegenerative diseases. We are pursuing the study of the role in the brain of tumor protein 53-induced nuclear protein 1 (TP53INP1), a stress-induced protein known to act as a dual regulator of transcription and of autophagy, whose deficiency has been linked to cancer and metabolic syndrome through mechanisms that are also involved in neurodegenerative diseases (including chronic inflammation, oxidative stress and autophagy dysregulation). In collaboration with the groups of Alice Carrier (CRCM, Marseille) and Olga Corti (ICM, Paris), we recently uncovered a neuroprotective role of TP53INP1 for dopamine neurons under aging and PD-related conditions and provided evidence that TP53INP1 might maintain neuronal homeostasis by adapting basal mitophagy demands via autophagy regulation (Dinh et al., 2021). Ongoing experiments investigate the impact of TP53INP1 deficiency in the context of aging- and AD-related cognitive impairments, in collaboration with the team of Pascale Durbec at the IBDM. We are also interested in mitochondrial dynamics, whose alteration has been implicated in neurodegenerative disorders and hereditary neuropathies. In particular, we are studying the consequences of mitochondrial fusion and fission imbalance in drosophila models of Charcot-Marie-Tooth neuropathy type 2A through a variety of in vivo approaches.

Mitochondrial network in living larval drosophila motor neurons
A rare observation of drosophila mitochondria staring into the eyes of the experimenter. Ⓒ Thomas Rival, IBDM

The second part aims at revisiting the involvement of the glutamate system in PD pathogenesis and pathophysiology. We previously developed a rat model mimicking the slowly progressing and asymmetrical degenerative process that characterize PD (Assous at al., 2014). In collaboration with the group of Franck Durif (University of Clermont Auvergne, CHU, CNRS), we are investigating the interhemispheric reactive changes affecting the main BG glutamate components in this model and their possible contribution to the evolution of nigrostriatal dopamine neuron death, using a combination of in vivo and ex-vivo approaches.

Progressive loss of dopamine neurons in the substantia nigra pars compacta (SNc delineated by dotted lines) in a model of PD based on dysfunction of excitatory amino acid transporters.
Progressive loss of dopamine neurons in the substantia nigra pars compacta (SNc delineated by dotted lines) in a model of PD based on dysfunction of excitatory amino acid transporters.

In parallel to these main research lines, we are involved in a collaborative project developed by Rosanna Dono in the team of Flavio Maina at the IBDM, which aims at improving the efficacy and safety of the cell-based replacement therapy for PD using human induced pluripotent stem cells (hiPSCs). The objective is to evaluate the potential of regulating the levels of glypican 4, a signaling modulator, as a strategy to foster hiPSCs differentiation towards the disease-relevant cell type, namely ventral midbrain dopamine neuron, and reduce their propensity to develop tumors upon brain transplantation in a rat PD model at different stages of in vitro differentiation (Corti et al., 2021).