Recovery of the full in vivo firing range in post-lesion surviving DA SN neurons associated with Kv4.3-mediated pacemaker plasticity
- Goethe University Frankfurt, Germany
- University of Alabama at Birmingham, United States
- Universidad San Pablo CEU, Spain
Abstract
Dopamine (DA) neurons in the substantia nigra (SN) control several essential functions, including the voluntary movement, learning and motivated behavior. Healthy DA SN neurons show diverse firing patterns in vivo, ranging from slow pacemaker-like activity (1-10 Hz) to transient high frequency bursts (<100 Hz), interspersed with pauses that can last hundreds of milliseconds. Recent in vivo patch experiments have started to reveal the subthreshold mechanisms underlying this physiological diversity, but the impact of challenges like cell loss on the in vivo activity of adult DA SN neurons, and how these may relate to behavioral disturbances, are still largely unknown. We investigated the in vivo electrophysiological properties of surviving SN DA neurons after partial unilateral 6-OHDA lesions, a single-hit, non-progressive model of neuronal cell loss. We show that mice subjected to this model have an initial motor impairment, measured by asymmetrical rotations in the open field test, which recovered over time. At 3 weeks post-lesion, when open field locomotion was strongly impaired, surviving DA SN neurons showed a compressed in vivo dynamic firing range, characterized by a 10-fold reduction of in vivo burst firing compared to controls. This in vivo phenotype was accompanied by pronounced in vitro pacemaker instability. In contrast, in the chronic post-lesion phase (>2 months), where turning symmetry in open field locomotion had recovered, surviving SN DA neurons displayed the full dynamic range of in vivo firing, including in vivo bursting, similar to controls. The normalized in vivo firing pattern was associated with a 2-fold acceleration of stable in vitro pacemaking, mediated by Kv4.3 potassium channel downregulation. Our findings demonstrate the existence of a homeostatic pacemaker plasticity mechanism in surviving DA SN neurons after pronounced cell loss.
Data availability
All data have been uploaded to Dryad. http://datadryad.org/share/RqbyPeiXI9lr_JlSE4XXxbvL65VwiUmtPlQ5UFndSdI
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Recovery of the full in vivo firing range in post-lesion surviving DA SN neurons associated with Kv4.3-mediated pacemaker plasticityDryad Digital Repository,DOI: 10.5061/dryad.76hdr7t6z.
Article and author information
Author details
Kauê Machado Costa
Funding
Deutsche Forschungsgemeinschaft (CRC1451,CRC1080)
- Jochen Roeper
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All involved animal experiments were approved by the state authorities. (RP Darmstadt)
Copyright
© 2025, Kovacheva et al.
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
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Recovery of the full in vivo firing range in post-lesion surviving DA SN neurons associated with Kv4.3-mediated pacemaker plasticity
eLife 14:e104037.
https://doi.org/10.7554/eLife.104037
