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Kv4.3 channel downregulation mediates chronic post-lesional pacemaker acceleration in surviving dopamine substantia nigra neurons

View ORCID ProfileLora Kovacheva, View ORCID ProfileJosef Shin, Navid Farassat, View ORCID ProfileJochen Roeper
doi: https://doi.org/10.1101/2021.08.09.455657
Lora Kovacheva
Institute of Neurophysiology, Neuroscience Center, Goethe University, Frankfurt, Germany
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  • For correspondence: roeper@em.uni-frankfurt.de lorask@gmail.com
Josef Shin
Institute of Neurophysiology, Neuroscience Center, Goethe University, Frankfurt, Germany
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Navid Farassat
Institute of Neurophysiology, Neuroscience Center, Goethe University, Frankfurt, Germany
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Jochen Roeper
Institute of Neurophysiology, Neuroscience Center, Goethe University, Frankfurt, Germany
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  • ORCID record for Jochen Roeper
  • For correspondence: roeper@em.uni-frankfurt.de lorask@gmail.com
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Abstract

Substantia nigra dopamine (SN DA) neurons are progressively lost in Parkinson disease (PD). While the molecular and cellular mechanisms of their differential vulnerability and degeneration have been extensively studied, we still know very little about potential functional adaptations of those SN DA neurons that – at least for some time – manage to survive during earlier stages of PD. We utilized a partial lesion 6-OHDA mouse model to characterize initial electrophysiological impairments and chronic adaptations of surviving identified SN DA neurons, both in vivo and in vitro. Early after lesion (3 weeks), we detected a selective loss of in vivo burst firing in surviving SN DA neurons, which was accompanied by in vitro pacemaker instability. In contrast, late after lesion (>2 months), in vivo firing properties of surviving SN DA neurons had recovered in the presence of 2-fold accelerated pacemaking in vitro. Finally, we show that this chronic cell-autonomous adaptation in surviving SN DA neurons was mediated by Kv4.3 channel downregulation. Our study demonstrates substantial homeostatic plasticity of surviving SN DA neurons after a single-hit non-progressive lesion, which might contribute to the phenotype of initially surviving SN DA neurons in PD.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted August 09, 2021.
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Kv4.3 channel downregulation mediates chronic post-lesional pacemaker acceleration in surviving dopamine substantia nigra neurons
Lora Kovacheva, Josef Shin, Navid Farassat, Jochen Roeper
bioRxiv 2021.08.09.455657; doi: https://doi.org/10.1101/2021.08.09.455657
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Kv4.3 channel downregulation mediates chronic post-lesional pacemaker acceleration in surviving dopamine substantia nigra neurons
Lora Kovacheva, Josef Shin, Navid Farassat, Jochen Roeper
bioRxiv 2021.08.09.455657; doi: https://doi.org/10.1101/2021.08.09.455657

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