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

Abstract

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.