1. Remote control of induced dopaminergic neurons in parkinsonian rats
- Author
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Liudmila Mus, Elena Dvoretskova, Ilda Theka, Damiana Leo, Alexander Dityatev, Raul R. Gainetdinov, Vania Broccoli, Gaia Colasante, Maria Teresa Dell’Anno, Stefano Taverna, Giovanni Russo, Serena Giannelli, Fabio Benfenati, Massimiliano Caiazzo, Gianni Pezzoli, Lucian Medrihan, Dell'Anno, Maria Teresa, Caiazzo, Massimiliano, Leo, Damiana, Dvoretskova, Elena, Medrihan, Lucian, Colasante, Gaia, Giannelli, Serena, Theka, Ilda, Russo, Giovanni, Mus, Liudmila, Pezzoli, Gianni, Gainetdinov, Raul R, Benfenati, Fabio, Taverna, Stefano, Dityatev, Alexander, and Broccoli, Vania
- Subjects
Male ,Dopamine ,Cell ,drug effects [Dopaminergic Neurons] ,physiopathology [Brain] ,pathology [Parkinsonian Disorders] ,Pharmacology ,Designer Drugs ,Cell therapy ,Mice ,pathology [Brain] ,analogs & derivatives [Clozapine] ,Premovement neuronal activity ,metabolism [Dopamine] ,Clozapine ,Mice, Knockout ,Dopaminergic ,Brain ,Parkinsonian Disorder ,genetics [Cell Transdifferentiation] ,General Medicine ,transplantation [Dopaminergic Neurons] ,medicine.anatomical_structure ,physiopathology [Parkinsonian Disorders] ,Female ,Rats, Transgenic ,Dopaminergic Neuron ,Reprogramming ,Human ,Research Article ,medicine.drug ,Cell signaling ,Designer Drug ,Biology ,Parkinsonian Disorders ,pharmacology [Clozapine] ,medicine ,Animals ,Humans ,ddc:610 ,physiology [Dopaminergic Neurons] ,therapy [Parkinsonian Disorders] ,Animal ,Dopaminergic Neurons ,Electrophysiological Phenomena ,Rats ,Disease Models, Animal ,nervous system ,clozapine N-oxide ,Cell Transdifferentiation ,Rat ,Neuron ,Neuroscience - Abstract
Direct lineage reprogramming through genetic-based strategies enables the conversion of differentiated somatic cells into functional neurons and distinct neuronal subtypes. Induced dopaminergic (iDA) neurons can be generated by direct conversion of skin fibroblasts; however, their in vivo phenotypic and functional properties remain incompletely understood, leaving their impact on Parkinson's disease (PD) cell therapy and modeling uncertain. Here, we determined that iDA neurons retain a transgene-independent stable phenotype in culture and in animal models. Furthermore, transplanted iDA neurons functionally integrated into host neuronal tissue, exhibiting electrically excitable membranes, synaptic currents, dopamine release, and substantial reduction of motor symptoms in a PD animal model. Neuronal cell replacement approaches will benefit from a system that allows the activity of transplanted neurons to be controlled remotely and enables modulation depending on the physiological needs of the recipient; therefore, we adapted a DREADD (designer receptor exclusively activated by designer drug) technology for remote and real-time control of grafted iDA neuronal activity in living animals. Remote DREADD-dependent iDA neuron activation markedly enhanced the beneficial effects in transplanted PD animals. These data suggest that iDA neurons have therapeutic potential as a cell replacement approach for PD and highlight the applicability of pharmacogenetics for enhancing cellular signaling in reprogrammed cell-based approaches.
- Published
- 2014
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