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Tetrodotoxin-resistant NaV1.5 channels regulate excitability of lateral septum neurons and emotion behaviors of chronically stressed mice

Molecular Psychiatry (2026)Cite this article

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Abstract

Lateral septum (LS) plays crucial roles in regulating various emotional behaviors. The molecular mechanism governing the excitability of LS neuron (LSN) remains unclear. Using single-nucleus RNA sequencing (snRNA-seq) and immunostaining, we detected high expression levels of Scn5a, the cardiac TTX-resistant voltage-gated Na+ channel (NaV) subtype across many transcriptomic LSN types, and accumulation of its channel protein NaV1.5 at the axon initial segment. Activation of NaV1.5 alone is sufficient to generate action potentials, particularly from a hyperpolarized membrane potential. Knocking out NaV1.5 from LSNs reduces spiking activity and decreases anxiety and depression levels in chronically stressed mice, but not in unstressed ones. Importantly, acute treatment with the antiarrhythmic agent flecainide can diminish the TTX-resistant currents and alleviate the anxiety- and depression-like behaviors of stressed mice. Together, our results reveal a critical role of NaV1.5 channels in governing LSN excitability and identify a potential drug target for a rapid control of emotional disorders.

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Fig. 1: Scn5a is expressed by various transcriptomic LSN subtypes and associated with emotional disorders.
Fig. 2: Distribution of Scn5a+ neurons in LS and accumulation of NaV1.5 channel protein at the AIS.
Fig. 3: TTX-resistant NaV1.5 currents support AP generation in LSNs.
Fig. 4: Deletion of Scn5a reduces the excitability of LSNs in chronically stressed mice, but not unstressed sham mice.
Fig. 5: Selective deletion of NaV1.5 from LSNs alleviates negative emotion behaviors in chronically stressed mice.
Fig. 6: Flecainide inhibits TTX-resistant NaV1.5 currents in LSNs and alleviates anxiety- and depression-like behaviors.

Data availability

All data reported in this paper will be shared by the lead contact upon request.

Code availability

The codes for RNA-seq data analysis are available at https://github.com/Shuxuan-Lyu/RNA-seq-analysis-scripts/tree/LS-Nav1.5-regulates-emotion-behaviors. The codes for electrophysiological data analysis are available at https://github.com/LeeJunloong/Action-potential-analysis and https://github.com/RegulusYuuki/Electrocardiogram_analysis_for_mice-MP2025.

References

  1. Malezieux M, Klein AS, Gogolla N. Neural circuits for emotion. Annu Rev Neurosci. 2023;46:211–31.

    Article  CAS  PubMed  Google Scholar 

  2. Parfitt GM, Nguyen R, Bang JY, Aqrabawi AJ, Tran MM, Seo DK, et al. Bidirectional control of anxiety-related behaviors in mice: role of inputs arising from the ventral hippocampus to the lateral septum and medial prefrontal cortex. Neuropsychopharmacology. 2017;42:1715–28.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Wang D, Pan X, Zhou Y, Wu Z, Ren K, Liu H, et al. Lateral septum-lateral hypothalamus circuit dysfunction in comorbid pain and anxiety. Mol Psychiatry. 2023;28:1090–1100. https://doi.org/10.1038/s41380-022-01922-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Wang D, Wang W, Jiang S, Ma H, Lian H, Meng F, et al. Regulation of depression-related behaviors by GABAergic neurons in the lateral septum through periaqueductal gray neuronal projections. J Psychiatr Res. 2021;137:202–14.

    Article  PubMed  Google Scholar 

  5. Sheehan TP, Chambers RA, Russell DS. Regulation of affect by the lateral septum: implications for neuropsychiatry. Brain Res Brain Res Rev. 2004;46:71–117.

    Article  PubMed  Google Scholar 

  6. Singewald GM, Rjabokon A, Singewald N, Ebner K. The modulatory role of the lateral septum on neuroendocrine and behavioral stress responses. Neuropsychopharmacology. 2011;36:793–804.

    Article  PubMed  Google Scholar 

  7. Wang M, Li P, Li Z, da Silva BS, Zheng W, Xiang Z, et al. Lateral septum adenosine A2A receptors control stress-induced depressive-like behaviors via signaling to the hypothalamus and habenula. Nat Commun. 2023;14:1880.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Li H, Sung HH, Lau CG. Activation of somatostatin-expressing neurons in the lateral septum improves stress-induced depressive-like behaviors in mice. Pharmaceutics. 2022;14:2253.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Reid CM, Ren Y, Xie Y, Garcίa MT, Tran D, Vu S, et al. Multimodal classification of neurons in the lateral septum. BioRxiv 2024.02.15.580381 [Preprint]. 2024. Available from: https://www.biorxiv.org/content/10.1101/2024.02.15.580381v1.

  10. Chen G, Lai S, Jiang S, Li F, Sun K, Wu X, et al. Cellular and circuit architecture of the lateral septum for reward processing. Neuron. 2024;112:2783–98.e9.

    Article  CAS  PubMed  Google Scholar 

  11. Besnard A, Gao Y, TaeWoo Kim M, Twarkowski H, Reed AK, Langberg T, et al. Dorsolateral septum somatostatin interneurons gate mobility to calibrate context-specific behavioral fear responses. Nat Neurosci. 2019;22:436–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Li L, Durand-de Cuttoli R, Aubry AV, Burnett CJ, Cathomas F, Parise LF, et al. Social trauma engages lateral septum circuitry to occlude social reward. Nature. 2023;613:696–703.

    Article  CAS  PubMed  Google Scholar 

  13. Anthony TE, Dee N, Bernard A, Lerchner W, Heintz N, Anderson DJ. Control of stress-induced persistent anxiety by an extra-amygdala septohypothalamic circuit. Cell. 2014;156:522–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Leo NS, De, Nogueira R, Schulkin J, Asok A, Leroy F. Corticotropin-releasing hormone signaling from prefrontal cortex to lateral septum suppresses interaction with familiar mice. Cell. 2023;186:4152–71.

    Article  Google Scholar 

  15. Azevedo EP, Tan B, Pomeranz LE, Ivan V, Fetcho R, Schneeberger M, et al. A limbic circuit selectively links active escape to food suppression. Elife. 2020;9:1–23.

    Article  Google Scholar 

  16. Oliveira VE, de M, Lukas M, Wolf HN, Durante E, Lorenz A, et al. Oxytocin and vasopressin within the ventral and dorsal lateral septum modulate aggression in female rats. Nat Commun. 2021;12:1–15.

    Article  Google Scholar 

  17. Huang T, Guan F, Licinio J, Wong ML, Yang Y. Activation of septal OXTr neurons induces anxiety- but not depressive-like behaviors. Mol Psychiatry. 2021;26:7270–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zhang Q, Xue Y, Wei K, Wang H, Ma Y, Wei Y, et al. Locus coeruleus-dorsolateral septum projections modulate depression-like behaviors via BDNF but not norepinephrine. Adv Sci. 2024;11:1–20.

    Google Scholar 

  19. Zimmer T, Haufe V, Blechschmidt S. Voltage-gated sodium channels in the mammalian heart. Glob Cardiol Sci Pract. 2014;2014:58.

    Article  Google Scholar 

  20. Hu W, Tian C, Li T, Yang M, Hou H, Shu Y. Distinct contributions of Nav1.6 and Nav1.2 in action potential initiation and backpropagation. Nat Neurosci. 2009;12:996–1002.

    Article  CAS  PubMed  Google Scholar 

  21. Li T, Tian C, Scalmani P, Frassoni C, Mantegazza M, Wang Y, et al. Action potential initiation in neocortical inhibitory interneurons. PLoS Biol. 2014;12:e1001944.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Heinle JW, Dalessio S, Janicki P, Ouyang A, Vrana KE, Ruiz-Velasco V, et al. Insights into the voltage-gated sodium channel, NaV1.8, and its role in visceral pain perception. Front Pharmacol. 2024;15:1–8.

    Article  Google Scholar 

  23. Kakimura JI, Zheng T, Uryu N, Ogata N. Regulation of the spontaneous augmentation of Nav1.9 in mouse dorsal root ganglion neurons: effect of PKA and PKC pathways. Mar Drugs. 2010;8:728–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hartmann HA, Colom LV, Sutherland ML, Noebels JL. Selective localization of cardiac SCN5A sodium channels in limbic regions of rat brain. Nat Neurosci. 1999;2:593–5.

    Article  CAS  PubMed  Google Scholar 

  25. Wang L, Simms J, Peters CJ, Fontaine MT, Li K, Gill TM, et al. TMEM16B calcium-activated chloride channels regulate action potential firing in lateral septum and aggression in male mice. J Neurosci. 2019;39:7102–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Alonso JR, Frotscher M. Organization of the septal region in the rat brain: a Golgi/EM study of lateral septal neurons. J Comp Neurol. 1989;286:472–87.

    Article  CAS  PubMed  Google Scholar 

  27. Bean BP. The action potential in mammalian central neurons. Nat Rev Neurosci. 2007;8:451–65.

    Article  CAS  PubMed  Google Scholar 

  28. Branco T, Tozer A, Magnus CJ, Sugino K, Tanaka S, Lee AK, et al. Near-Perfect synaptic integration by Na v 1.7 in hypothalamic neurons regulates body weight. Cell. 2016;165:1749–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Shin S, Pribiag H, Lilascharoen V, Knowland D, Wang XY, Lim BK. Drd3 signaling in the lateral septum mediates early life stress-induced social dysfunction. Neuron. 2018;97:195–208.e6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kole MHP, Stuart GJ. Signal processing in the axon initial segment. Neuron. 2012;73:235–47.

    Article  CAS  PubMed  Google Scholar 

  31. Leterrier C The axon initial segment, 50 years later. Curr Top Membr, 77, Elsevier Ltd; 2016. pp. 185–233.

  32. Resch JM, Fenselau H, Madara JC, Wu C, Campbell JN, Lyubetskaya A, et al. Aldosterone-Sensing neurons in the NTS exhibit state-dependent pacemaker activity and drive sodium appetite via synergy with angiotensin II Signaling. Neuron. 2017;96:190–206.e7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. da Mata DO, Tibery DV, Campos LA, Camargos TS, Peigneur S, Tytgat J, et al. Subtype specificity of β-toxin Tf1a from Tityus fasciolatus in voltage gated sodium channels. Toxins. 2018;10:339.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Liu WZ, Wang CY, Wang Y, Cai MT, Zhong WX, Liu T, et al. Circuit- and laminar-specific regulation of medial prefrontal neurons by chronic stress. Cell Biosci. 2023;13:1–14.

    Article  Google Scholar 

  35. Rodrigues TB, Ballesteros P. Optimization of chronic stress paradigms using anxiety- and depression-like behavioral parameters. J Neurosci Res. 2007;3253:3244–53.

    Google Scholar 

  36. Amin AS, Tan HL, Wilde AAM. Cardiac ion channels in health and disease. Hear Rhythm. 2010;7:117–26.

    Article  Google Scholar 

  37. Remme CA, Bezzina CR. Sodium channel (dys)function and cardiac arrhythmias. Cardiovasc Ther. 2010;28:287–94.

    Article  PubMed  Google Scholar 

  38. Osawa Y, Oda A, Iida H, Tanahashi S, Dohi S. The effects of class Ic antiarrhythmics on tetrodotoxin-resistant Na + currents in rat sensory neurons. Anesth Analg. 2004;99:464–71.

    Article  CAS  PubMed  Google Scholar 

  39. Ramos E, O’Leary ME. State‐dependent trapping of flecainide in the cardiac sodium channel. J Physiol. 2004;560:37–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Piovan D, Padrini R, Furlanut M, Moretto R, Ferrari M. Plasma and tissue levels of flecainide in rats. Pharmacol Res Commun. 1986;18:739–45.

    Article  CAS  PubMed  Google Scholar 

  41. Liu N, Denegri M, Ruan Y, Avelino-Cruz JE, Perissi A, Negri S, et al. Short communication: flecainide exerts an antiarrhythmic effect in a mouse model of catecholaminergic polymorphic ventricular tachycardia by increasing the threshold for triggered activity. Circ Res. 2011;109:291–5.

    Article  CAS  PubMed  Google Scholar 

  42. Bienkowski MS, Bowman I, Song MY, Gou L, Ard T, Cotter K, et al. Integration of gene expression and brain-wide connectivity reveals the multiscale organization of mouse hippocampal networks. Nat Neurosci. 2018;21:1628–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Besnard A, Leroy F. Top-down regulation of motivated behavior via the lateral septum. Mol Psychiatry. 2022;27:3119–28.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Rizzi-Wise CA, Wang DV. Putting Together Pieces of the Lateral Septum: Multifaceted Functions and Its Neural Pathways. Eneuro. 2021;8:ENEURO.0315–21.2021.

    Article  PubMed  Google Scholar 

  45. Risold PY, Swanson LW. Chemoarchitecture of the rat lateral septal nucleus. Brain Res Rev. 1997;24:91–113.

    Article  CAS  PubMed  Google Scholar 

  46. Platkiewicz J, Brette R. A threshold equation for action potential initiation. PLoS Comput Biol. 2010;6:e1000850.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Dautzenberg FM, Hauger RL. The CRF peptide family and their receptors: yet more partners discovered. Trends Pharmacol Sci. 2002;23:71–77.

    Article  CAS  PubMed  Google Scholar 

  48. Iqbal SM, Lemmens-Gruber R. Phosphorylation of cardiac voltage-gated sodium channel: Potential players with multiple dimensions. Acta Physiol. 2019;225:e13210.

    Article  Google Scholar 

  49. Verkerk AO, Amin AS, Remme CA. Disease modifiers of inherited SCN5A channelopathy. Front Cardiovasc Med. 2018;5:137.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Plijter IS, Verkerk AO, Wilders R. The antidepressant paroxetine reduces the cardiac sodium current. Int J Mol Sci. 2023;24:1904.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Poulin H, Bruhova I, Timour Q, Theriault O, Beaulieu J-M, Frassati D, et al. Fluoxetine blocks Nav1.5 channels via a mechanism similar to that of class 1 antiarrhythmics. Mol Pharmacol. 2014;86:378–89.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Hsueh B, Chen R, Jo YJ, Tang D, Raffiee M, Kim YS, et al. Cardiogenic control of affective behavioural state. Nature. 2023;615:292–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Hashimoto M, Brito SI, Venner A, Pasqualini AL, Yang TL, Allen D, et al. Lateral septum modulates cortical state to tune responsivity to threat stimuli. Cell Rep. 2022;41:111521.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Chen S, Zhou Y, Chen Y, Gu J. Fastp: an ultra-fast all-in-one FASTQ preprocessor. Bioinformatics. 2018;34:i884–i890.

    Article  PubMed  PubMed Central  Google Scholar 

  55. McGinnis CS, Murrow LM, Gartner ZJ. DoubletFinder: doublet detection in single-cell RNA sequencing data using artificial nearest neighbors. Cell Syst. 2019;8:329–337.e4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Hao Y, Hao S, Andersen-Nissen E, Mauck WM, Zheng S, Butler A, et al. Integrated analysis of multimodal single-cell data. Cell. 2021;184:3573–87.e29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Korsunsky I, Millard N, Fan J, Slowikowski K, Zhang F, Wei K, et al. Fast, sensitive and accurate integration of single-cell data with Harmony. Nat Methods. 2019;16:1289–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Morabito S, Reese F, Rahimzadeh N, Miyoshi E, Swarup V. hdWGCNA identifies co-expression networks in high-dimensional transcriptomics data. Cell Rep Methods. 2023;3:100498.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Li J, Deng S, He Q, Ke W, Shu Y Asynchronous glutamate release at autapses regulates spike reliability and precision in mouse neocortical pyramidal cells. Cereb Cortex. 2020:1–13.

  60. Dumenieu M, Senkov O, Mironov A, Bourinet E, Kreutz MR, Dityatev A, et al. The low-threshold calcium channel Cav3.2 mediates burst firing of mature dentate granule cells. Cereb Cortex. 2018;28:2594–609.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Yang Y, Cui Y, Sang K, Dong Y, Ni Z, Ma S, et al. Ketamine blocks bursting in the lateral habenula to rapidly relieve depression. Nature. 2018;554:317–22.

    Article  CAS  PubMed  Google Scholar 

  62. Bachmanov AA, Reed DR, Beauchamp GK, Tordoff MG. Food intake, water intake, and drinking spout side preference of 28 mouse strains. Behav Genet. 2012;32:25–29.

    Google Scholar 

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Acknowledgements

This study was supported by National Natural Science Foundation of China (NSFC grants: 32130044 and T2241002, Y.S.), STI2030-Major Projects (2021ZD0202500, Y.S.), the National Key R&D Program of China (2024YFF0507601, Y.S.), Changping Laboratory (2025B-07-21, Y.S.) and Program of Shanghai Academic/Technology Research Leader (21XD1400100, Y.S.), as well as NSFC grant (32200951 to Y.X. and 32500857 to S.L.), and China Postdoctoral Science Foundation (2022M720801 to Y.X. and 2023M740657 to S.L.).

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Author notes

  1. Junlong Li

    Present address: Center for NeuroMetabolism, Child Health Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, 08901, USA

  2. These authors contributed equally: Junlong Li, Yujie Xiao, Shuxuan Lyu.

Authors and Affiliations

  1. Department of Neurology, Jinshan Hospital, Institute for Translational Brain Research, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, MOE Innovative Center for New Drug Development of Immune Inflammatory Diseases, Fudan University, Shanghai, 201508, China

    Junlong Li, Yujie Xiao, Shuxuan Lyu, Kun Wang, Heyuan Zhang, Yuxiang Zheng, Xiaoxue Zhang, Hongkun Yang & Yousheng Shu

  2. College of Elementary Education, Capital Normal University, Beijing, 100048, China

    Yujie Xiao

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Contributions

Y.S. conceived and designed the study. J.L. performed most of the experiments and analyzed the data. Y.X., K.W. and Y.Z. helped in the electrophysiological experiments, behavior tests, and data analysis. S.L. performed analysis of the snRNA-seq data. X.Z. helped in behavior tests. H.Z and H.Y. helped in electrophysiological experiments. J.L., Y.X., S.L. and Y.S. wrote the manuscript. All authors edited the manuscript.

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Correspondence to Yousheng Shu.

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Li, J., Xiao, Y., Lyu, S. et al. Tetrodotoxin-resistant NaV1.5 channels regulate excitability of lateral septum neurons and emotion behaviors of chronically stressed mice. Mol Psychiatry (2026). https://doi.org/10.1038/s41380-026-03453-2

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