The sodium leak channel NALCN in Drd2+ striatal neurons regulates neuronal excitability, locomotion and food-seeking in a sex-dependent manner

1. Neuropsychopharmacology. 2026 Feb 11. doi: 10.1038/s41386-026-02363-9. Online
ahead of print.

The sodium leak channel NALCN in Drd2(+) striatal neurons regulates neuronal
excitability, locomotion and food-seeking in a sex-dependent manner.

Castell L(#)(1)(2), Naon C(#)(3), Rogliardo A(3), Ducrocq F(4), Makrini L(3),
Typou A(1), Avrillon M(3), Mignon A(3), Bernat C(1), Lory P(1), Bertaso F(3),
Monteil A(1)(5), Bosch-Bouju C(6), Valjent E(7).

Author information:
(1)IGF, Univ. Montpellier, CNRS, Inserm, Montpellier, France.
(2)Department of Neuroscience, Northwestern University Feinberg School of
Medicine, Chicago, IL, USA.
(3)INM, Univ. Montpellier, Inserm, Montpellier, France.
(4)Université Bordeaux, INRAE, Bordeaux INP, NutriNeuro, Bordeaux, France.
(5)Department of Physiology, Faculty of Medicine Siriraj Hospital, Mahidol
University, Bangkok, Thailand.
(6)Université Bordeaux, INRAE, Bordeaux INP, NutriNeuro, Bordeaux, France.
.
(7)INM, Univ. Montpellier, Inserm, Montpellier, France.
.
(#)Contributed equally

The sodium leak channel NALCN is an important modulator of cell excitability.
Studies so far demonstrated the critical role of this highly conserved channel
in the generation and maintenance of pacemaker activity in cells with
spontaneous firing, such as cardiomyocytes, adrenal cells, or neurons. However,
the physiological importance of NALCN for neurons with no spontaneous firing has
been largely overlooked and remains unknown. Yet, Drd2-expressing striatal
projection neurons (SPNs) show an enriched expression of NALCN while they are
highly hyperpolarized neurons. Considering that pathogenic variants of NALCN in
human result in severe pathological conditions with symptoms that include
cognitive and motor impairments, we hypothesized that NALCN in Drd2-SPNs was
necessary for their correct signal integration and consequently
striatal-associated behaviors. Here, we investigated the impact of NALCN
deletion in Drd2-SPNs in both male and female mice. Unexpectedly, we found that
only male mice with deletion of NALCN in Drd2-expressing neurons exhibited
enhanced locomotor responses to novel environment and reduced motivation in
food-seeking tasks, while female mice were unaffected in their behavior.
Similarly, electrophysiological recordings of SPNs revealed significant sex
differences, with male SPNs lacking NALCN exhibiting altered membrane properties
and increased excitability, while females showed only subtle changes. Finally,
we found that eticlopride-induced catalepsy and signaling events were
differently altered by NALCN deletion in Drd2-SPNs male and female mice. This
work constitutes the first evidence that NALCN in Drd2-SPNs participates to
striatal function and may be a key modulator of response to antidopaminergic
treatments, with significant sex differences.

© 2026. The Author(s), under exclusive licence to American College of
Neuropsychopharmacology.

DOI: 10.1038/s41386-026-02363-9
PMID: 41673358

Conflict of interest statement: Competing interests: The authors declare no
competing interests.

Auteurs Bordeaux Neurocampus