Electrophysiological characterisation of intranigral-grafted hiPSC-derived dopaminergic neurons in a mouse model of Parkinson’s disease
Abstract Background Parkinson’s disease (PD) is a complex neurological disorder characterized by the progressive degeneration of midbrain dopaminergic (mDA) neurons in the substantia nigra (SN). This degeneration disrupts the basal ganglia loops, leading to both motor and non-motor dysfunctions. Cel...
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2025-05-01
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| Online Access: | https://doi.org/10.1186/s13287-025-04344-z |
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| author | Bérengère Ballion Marie-Laure Bonnet Sébastien Brot Afsaneh Gaillard |
| author_facet | Bérengère Ballion Marie-Laure Bonnet Sébastien Brot Afsaneh Gaillard |
| author_sort | Bérengère Ballion |
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| description | Abstract Background Parkinson’s disease (PD) is a complex neurological disorder characterized by the progressive degeneration of midbrain dopaminergic (mDA) neurons in the substantia nigra (SN). This degeneration disrupts the basal ganglia loops, leading to both motor and non-motor dysfunctions. Cell therapy for PD aims to replace lost mDA neurons to restore the DA neurotransmission in the denervated forebrain targets. In clinical trials for PD, mDA neurons are implanted into the target area, the striatum, and not in the SN where they are normally located. This ectopic localisation of cells may affect the functionality of transplanted neurons due to the absence of appropriate host afferent regulation. We recently demonstrated that human induced pluripotent stem cells (hiPSCs) derived mDA progenitors grafted into the substantia nigra pars compacta (SNpc) in a mouse model of PD, differentiated into mature mDA neurons, restored the degenerated nigrostriatal pathway, and induced motor recovery. The objective of the present study was to evaluate the long-term functionality of these intranigral-grafted mDA neurons by assessing their electrophysiological properties. Methods We performed intranigral transplantation of hiPSC-derived mDA progenitors in a 6-hydroxydopamine RAG2-KO mouse model of PD. We recorded in vivo unit extracellular activity of grafted mDA neurons in anesthetised mice from 9 to 12 months post-transplantation. Their electrophysiological properties, including firing rates, patterns and spike characteristics, were analysed and compared with those of native nigral dopaminergic neurons from control mice. Results We demonstrated that these grafted mDA neurons exhibited functional characteristics similar to those of native nigral dopaminergic neurons, such as large bi- or triphasic spike waveforms, low firing rates, pacemaker-like properties, and two single-spike firing patterns. Although grafted mDA neurons also displayed low discharge frequencies below 10 Hz, their mean frequency was significantly lower than that of nigral mDA neurons, with a differential pattern distribution. Conclusions Our findings indicate that grafted mDA neurons exhibit dopaminergic-like functional properties, including intrinsic membrane potential oscillations leading to regular firing patterns. Additionally, they demonstrated irregular and burst firing patterns, suggesting they receive modulatory inputs. However, grafted mDA neurons displayed distinct properties, potentially related to their human origin or the incomplete maturation one year after transplantation. |
| format | Article |
| id | doaj-art-aeeac970cdce457ea8b9db304fde4eba |
| institution | OA Journals |
| issn | 1757-6512 |
| language | English |
| publishDate | 2025-05-01 |
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| spelling | doaj-art-aeeac970cdce457ea8b9db304fde4eba2025-08-20T01:49:42ZengBMCStem Cell Research & Therapy1757-65122025-05-0116112210.1186/s13287-025-04344-zElectrophysiological characterisation of intranigral-grafted hiPSC-derived dopaminergic neurons in a mouse model of Parkinson’s diseaseBérengère Ballion0Marie-Laure Bonnet1Sébastien Brot2Afsaneh Gaillard3Laboratoire des neurosciences expérimentales et cliniques (LNEC), Université de Poitiers– INSERM 1084Laboratoire des neurosciences expérimentales et cliniques (LNEC), Université de Poitiers– INSERM 1084Laboratoire des neurosciences expérimentales et cliniques (LNEC), Université de Poitiers– INSERM 1084Laboratoire des neurosciences expérimentales et cliniques (LNEC), Université de Poitiers– INSERM 1084Abstract Background Parkinson’s disease (PD) is a complex neurological disorder characterized by the progressive degeneration of midbrain dopaminergic (mDA) neurons in the substantia nigra (SN). This degeneration disrupts the basal ganglia loops, leading to both motor and non-motor dysfunctions. Cell therapy for PD aims to replace lost mDA neurons to restore the DA neurotransmission in the denervated forebrain targets. In clinical trials for PD, mDA neurons are implanted into the target area, the striatum, and not in the SN where they are normally located. This ectopic localisation of cells may affect the functionality of transplanted neurons due to the absence of appropriate host afferent regulation. We recently demonstrated that human induced pluripotent stem cells (hiPSCs) derived mDA progenitors grafted into the substantia nigra pars compacta (SNpc) in a mouse model of PD, differentiated into mature mDA neurons, restored the degenerated nigrostriatal pathway, and induced motor recovery. The objective of the present study was to evaluate the long-term functionality of these intranigral-grafted mDA neurons by assessing their electrophysiological properties. Methods We performed intranigral transplantation of hiPSC-derived mDA progenitors in a 6-hydroxydopamine RAG2-KO mouse model of PD. We recorded in vivo unit extracellular activity of grafted mDA neurons in anesthetised mice from 9 to 12 months post-transplantation. Their electrophysiological properties, including firing rates, patterns and spike characteristics, were analysed and compared with those of native nigral dopaminergic neurons from control mice. Results We demonstrated that these grafted mDA neurons exhibited functional characteristics similar to those of native nigral dopaminergic neurons, such as large bi- or triphasic spike waveforms, low firing rates, pacemaker-like properties, and two single-spike firing patterns. Although grafted mDA neurons also displayed low discharge frequencies below 10 Hz, their mean frequency was significantly lower than that of nigral mDA neurons, with a differential pattern distribution. Conclusions Our findings indicate that grafted mDA neurons exhibit dopaminergic-like functional properties, including intrinsic membrane potential oscillations leading to regular firing patterns. Additionally, they demonstrated irregular and burst firing patterns, suggesting they receive modulatory inputs. However, grafted mDA neurons displayed distinct properties, potentially related to their human origin or the incomplete maturation one year after transplantation.https://doi.org/10.1186/s13287-025-04344-zParkinson’s diseaseCell therapyHiPSCIntranigral transplantationMouseElectrophysiology |
| spellingShingle | Bérengère Ballion Marie-Laure Bonnet Sébastien Brot Afsaneh Gaillard Electrophysiological characterisation of intranigral-grafted hiPSC-derived dopaminergic neurons in a mouse model of Parkinson’s disease Stem Cell Research & Therapy Parkinson’s disease Cell therapy HiPSC Intranigral transplantation Mouse Electrophysiology |
| title | Electrophysiological characterisation of intranigral-grafted hiPSC-derived dopaminergic neurons in a mouse model of Parkinson’s disease |
| title_full | Electrophysiological characterisation of intranigral-grafted hiPSC-derived dopaminergic neurons in a mouse model of Parkinson’s disease |
| title_fullStr | Electrophysiological characterisation of intranigral-grafted hiPSC-derived dopaminergic neurons in a mouse model of Parkinson’s disease |
| title_full_unstemmed | Electrophysiological characterisation of intranigral-grafted hiPSC-derived dopaminergic neurons in a mouse model of Parkinson’s disease |
| title_short | Electrophysiological characterisation of intranigral-grafted hiPSC-derived dopaminergic neurons in a mouse model of Parkinson’s disease |
| title_sort | electrophysiological characterisation of intranigral grafted hipsc derived dopaminergic neurons in a mouse model of parkinson s disease |
| topic | Parkinson’s disease Cell therapy HiPSC Intranigral transplantation Mouse Electrophysiology |
| url | https://doi.org/10.1186/s13287-025-04344-z |
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