Functional integration of grafted hiPSC derived dopamine neurons in a murine model of Parkinson's disease

Autor: Ballion, Bérangère, Belnoue, Laure, Brot, Sébastien, Gaillard, Afsaneh
Přispěvatelé: Université de Poitiers - Faculté de Sciences fondamentales et appliquées, Université de Poitiers, Laboratoire de neurosciences expérimentales et cliniques (LNEC), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire de Poitiers (CHU Poitiers), BALLION, Bérangère
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: NeuroFrance 2021
NeuroFrance 2021, May 2021, Strasbourg, France
NeurFrance 2021
NeurFrance 2021, May 2021, Strasbourg, France
Popis: International audience; Parkinson´s disease (PD) is mainly characterized by a progressive degeneration of mesencephalic dopaminergic (DA) neurons of the substancia nigra pars compacta (SNc). Loss of DA neurons induces major imbalances of basal ganglia loop activity resulting in motor and cognitive symptoms. Therapeutic proposals are multiple but among the most promising ones, the cell therapy is emerging as a major research axis. In this context, we propose to study the functional integration of DA progenitor neurons derived human induced-pluripotent stem cells (hiPSCs) grafted into the SN in the 6-OHDA lesioned RAG2-KO mouse model of PD.In this project, we investigated the physiological functionality of the grafted-DA neurons, eight to nine months post-transplantation, by performing unit extracellular recordings in anesthetized mice to compare their electrophysiological characteristics to those collected in intact mice. Analysis of discharge activities (burst and irregular ones) and action potential (AP) shapes highlight that grafted-DA neurons show similar electrophysiological activities to that of native-DA neurons. These data point to an effective maturation of grafted DA neurons.Because the striatum is the main target structure of nigral dopaminergic inputs, we aim to question in a second step, the restoration of the dorsolateral medium spiny neuron (MSNs) activities, as well spontaneous and cortical-evoked ones which are imbalanced in absence of DA in our PD model. We assume that dopamine release from grafted-DA neurons readjusts the MSN activity and for the purpose, our future experimental strategy is to set up optogenetics coupled with electrophysiological in order to light manipulate the grafted-DA neurons expressing photosensible ArchT channels and to observe the electrophysiological consequences on the MSN activity. For this purpose, we´re developing actually the combined approach setup using a model of C57BL/6JRj mouse in which an AAV-ArchT-GFP construct is injected in the SNc: our first results show that with a defined 550nm light stimulation pattern, we can inhibit transfected-AAV-ArchT-GFP DA neurons recorded spontaneous activity in anaesthetized mouse. This technical data is major for the study and will be apply to transplanted-DA RAG2-KO mice.
Databáze: OpenAIRE
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