Deletion of the sodium leak channel NALCN in dopamine neurons alters D2R-mediated signalling and psychostimulant responsiveness.
8 affiliations
- 1INM, University Montpellier, Inserm, Montpellier, France.
- 2Plasticité du Cerveau CNRS UMR8249, École supérieure de physique et de chimie industrielles de la Ville de Paris (ESPCI), Paris, France.
- 3Neurocentre Magendie, U1215, University Bordeaux, INSERM, Bordeaux, France.
- 4Unité de Biologie Fonctionnelle et Adaptative, Université Paris Cité, CNRS, Paris, France.
- 5IGF, University Montpellier, CNRS, Inserm, Montpellier, France.
- 6Department of Physiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
- 7Institut Universitaire de France (IUF), Paris, France.
- 8Neuroscience Paris Seine CNRS UMR 8246 INSERM U1130, Institut de Biologie Paris Seine, Sorbonne Université, Paris, France.
Abstract
Midbrain dopamine (DA)-neurons are slow pacemakers that continuously fire action potentials, maintaining basal extracellular DA levels in target regions. The sodium leak channel NALCN has been identified as a key contributor in the pacemaker control of these neurons. However, the consequences of a disrupted DA pacemaker activity remain largely unexplored. By generating mice lacking NALCN selectively in midbrain DA-neurons, we investigated the impact of this deletion on the activity of ventral tegmental area DA-neurons, D2R-mediated signalling, reactivity to cues predicting threat and psychostimulant responsiveness in both males and females. Selective deletion of NALCN in midbrain DA-neurons dampens their tonic activity, without reducing the basal extracellular DA levels in the nucleus accumbens. Mice with a loss of NALCN in DA-neurons exhibit no impairments of basal motor responses, unaltered reactivity to cues predicting threat and risk assessment, while the neurochemical and behavioural responsiveness to psychostimulant drugs are enhanced and presynaptic D2R-mediated signalling at DA terminals is altered. Together, our results emphasize the important role of NALCN conductance in controlling DA pacemaker activity, D2R-mediated signalling and in modulating motor responses to psychostimulants. KEY POINTS: The sodium leak channel NALCN is an important contributor to the spontaneous pacemaker activity in dopamine neurons, but the consequences of its loss in these neurons remain largely unknown. We investigated how selective deletion of NALCN in dopamine neurons affects neuronal activity, dopamine receptor signalling and behavioural responses in male and female mice. Loss of NALCN markedly reduced the spontaneous activity of dopamine neurons, yet basal motor function, reward-related responses and reactivity to threat-predicting cues remained largely preserved. In contrast, neurochemical and behavioural responsiveness to psychostimulant drugs are enhanced, probably through an altered presynaptic D2R-mediated signalling at DA terminals. NALCN emerges as a key regulator of dopamine neuron activity, with disrupted pacemaker firing selectively enhancing psychostimulant sensitivity.
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BibTeX
@article{rogliardo2026deletion,
title = {{Deletion of the sodium leak channel NALCN in dopamine neurons alters D2R-mediated signalling and psychostimulant responsiveness.}},
author = {Angelina Rogliardo and Tinaig Le Borgne and Aylin Gulmez and Adeline Cathala and Claire Naon and Audrey Mignon and Maëlle Avrillon and Nejmeh Mashhour and Laia Castell and Claire Bernat and Jean-Michel Revest and Arnaud Monteil and Philippe Faure and Federica Bertaso and Giuseppe Gangarossa and Fabio Marti and Emmanuel Valjent},
journal = {The Journal of physiology},
year = {2026},
month = oct,
doi = {10.1113/jp289809},
url = {https://europepmc.org/article/MED/42837280},
note = {CC BY},
}
RIS
TY - JOUR
TI - Deletion of the sodium leak channel NALCN in dopamine neurons alters D2R-mediated signalling and psychostimulant responsiveness.
AU - Angelina Rogliardo
AU - Tinaig Le Borgne
AU - Aylin Gulmez
AU - Adeline Cathala
AU - Claire Naon
AU - Audrey Mignon
AU - Maëlle Avrillon
AU - Nejmeh Mashhour
AU - Laia Castell
AU - Claire Bernat
AU - Jean-Michel Revest
AU - Arnaud Monteil
AU - Philippe Faure
AU - Federica Bertaso
AU - Giuseppe Gangarossa
AU - Fabio Marti
AU - Emmanuel Valjent
PY - 2026
DA - 2026/10/06
JO - The Journal of physiology
DO - 10.1113/jp289809
UR - https://europepmc.org/article/MED/42837280
AB - Midbrain dopamine (DA)-neurons are slow pacemakers that continuously fire action potentials, maintaining basal extracellular DA levels in target regions. The sodium leak channel NALCN has been identified as a key contributor in the pacemaker control of these neurons. However, the consequences of a disrupted DA pacemaker activity remain largely unexplored. By generating mice lacking NALCN selectively in midbrain DA-neurons, we investigated the impact of this deletion on the activity of ventral tegmental area DA-neurons, D2R-mediated signalling, reactivity to cues predicting threat and psychostimulant responsiveness in both males and females. Selective deletion of NALCN in midbrain DA-neurons dampens their tonic activity, without reducing the basal extracellular DA levels in the nucleus accumbens. Mice with a loss of NALCN in DA-neurons exhibit no impairments of basal motor responses, unaltered reactivity to cues predicting threat and risk assessment, while the neurochemical and behavioural responsiveness to psychostimulant drugs are enhanced and presynaptic D2R-mediated signalling at DA terminals is altered. Together, our results emphasize the important role of NALCN conductance in controlling DA pacemaker activity, D2R-mediated signalling and in modulating motor responses to psychostimulants. KEY POINTS: The sodium leak channel NALCN is an important contributor to the spontaneous pacemaker activity in dopamine neurons, but the consequences of its loss in these neurons remain largely unknown. We investigated how selective deletion of NALCN in dopamine neurons affects neuronal activity, dopamine receptor signalling and behavioural responses in male and female mice. Loss of NALCN markedly reduced the spontaneous activity of dopamine neurons, yet basal motor function, reward-related responses and reactivity to threat-predicting cues remained largely preserved. In contrast, neurochemical and behavioural responsiveness to psychostimulant drugs are enhanced, probably through an altered presynaptic D2R-mediated signalling at DA terminals. NALCN emerges as a key regulator of dopamine neuron activity, with disrupted pacemaker firing selectively enhancing psychostimulant sensitivity.
SN - 0022-3751
SN - 1469-7793
ER -