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  3. Loss of sodium leak channel (NALCN) in the ventral dentate gyrus impairs neuronal activity of the glutamatergic neurons for inflammation-induced depression in male mice

Loss of sodium leak channel (NALCN) in the ventral dentate gyrus impairs neuronal activity of the glutamatergic neurons for inflammation-induced depression in male mice

  • Brain Behav Immun. 2023 Feb 14;S0889-1591(23)00038-7. doi: 10.1016/j.bbi.2023.02.013.
Jinping Wang 1,  Yaoxin Yang 2,  Jin Liu 1,  Jingxuan Qiu 1,  Donghang Zhang 3,  Mengchan Ou 2,  Yi Kang 2,  Tao Zhu 4,  Cheng Zhou 5
Affiliations

Affiliations

  • 1 Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, 610041, China; Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 2 Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 3 Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 4 Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: xwtao.zhu@foxmail.com.
  • 5 Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: zhouc@163.com.
PMID: 36796706 DOI: 10.1016/j.bbi.2023.02.013
Abstract

Background: The dentate gyrus (DG) has been implicated in the pathophysiology of depression. Many studies have revealed the cellular types, neural circuits, and morphological changes of the DG involved in the development of depression. However, the molecular regulating its intrinsic activity in depression is unknown.

Methods: Utilizing the mode of depression induced by lipopolysaccharide (LPS), we investigate the involvement of the sodium leak channel (NALCN) in inflammation-induced depressive-like behaviors of male mice. The expression of NALCN was detected by immunohistochemistry and real-time polymerase chain reaction. DG microinjection of the adeno-associated virus or lentivirus was carried out using a stereotaxic instrument and followed by behavioral tests. Neuronal excitability and NALCN conductance were recorded by whole-cell patch-clamp techniques.

Results: The expression and function of NALCN were reduced in both the dorsal and ventral DG in LPS-treated mice; whereas, only knocking down NALCN in the ventral pole produced depressive-like behaviors and this effect of NALCN was specific to ventral glutamatergic neurons. The excitability of ventral glutamatergic neurons was impaired by both the knockdown of NALCN and/or the treatment of LPS. Then, the overexpression of NALCN in the ventral glutamatergic neurons decreased the susceptibility of mice to inflammation-induced depression, and the intracranial injection of substance P (non-selective NALCN activator) into the ventral DG rapidly ameliorated inflammation-induced depression-like behaviors in an NALCN-dependent manner.

Conclusions: NALCN, which drives the neuronal activity of the ventral DG glutamatergic neurons, uniquely regulates depressive-like behaviors and susceptibility to depression. Therefore, the NALCN of glutamatergic neurons in the ventral DG may present a molecular target for rapid antidepressant drugs.

Keywords

dentate gyrus; depression; glutamatergic neurons; lipopolysaccharide; sodium leak channel; substance P.

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