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Gαq protein signaling in the bed nucleus of the stria terminalis regulate the lipopolysaccharide-induced despair-like behavior in mice

  • Nao Fukuwada and Miki Kanno contributed equally to this work.

  • Received: 24 August 2020 Accepted: 05 November 2020 Published: 10 November 2020
  • Major depressive disorder (MDD) is highly comorbid with anxiety disorders. It has been reported that the bed nucleus of the stria terminalis (BNST) is important for the induction of anxiety and MDD. Recently, the Gαq protein signaling within the BNST is involved in the induction of anxiety through Gαq protein signaling-mediated RNA-editing of GluR2 subunit, which produces the calcium (Ca2+)-impermeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor. On the other hand, the role of Gαq protein signaling within the BNST on the induction of MDD has never been reported yet. Therefore, we investigated whether Gαq protein signaling-producing the Ca2+-impermeable AMPA receptors in the BNST is involved in the lipopolysaccharide (LPS)-induced depressive-like behavior, particularly, despair-like behavior. When mice were systemically challenged with a single dose of LPS (1.2 mg/kg, i.p.), the immobility time during tail suspension test (TST) was increased 24 h after LPS injection. However, pretreatment with bilateral intra-BNST injection of neomycin (6.5 mM, 0.125 µL/side), an inhibitor of phospholipase C that is activated by Gαq protein-coupled receptor stimulation, extended the LPS-induced increase in the immobility time of TST. Furthermore, the co-pretreatment with bilateral intra-BNST injection of neomycin with 1-naphthylacetyl spermine (3 mM, 0.125 µL/side), an antagonist of Ca2+-permeable AMPA receptor, to mimic one of the final forms of Gαq protein activation, abolished the aggravated effect of neomycin and significantly shortened the immobility time compared with the control mice with an intra-BNST injection of artificial cerebrospinal fluid before LPS injection. However, pretreatment with bilateral intra-BNST injection of MDL-12,330A (10 µM, 0.125 µL/side), an inhibitor of adenylyl cyclase that is activated by Gαs protein-coupled receptor stimulation, did not affect the LPS-induced increase in the immobility time of TST. These results indicate that the Gαq protein signaling-mediated RNA-editing of GluR2, which produces the Ca2+-impermeable AMPA receptors within the BNST, regulates the LPS-induced despair-like behavior.

    Citation: Nao Fukuwada, Miki Kanno, Satomi Yoshida, Kenjiro Seki. Gαq protein signaling in the bed nucleus of the stria terminalis regulate the lipopolysaccharide-induced despair-like behavior in mice[J]. AIMS Neuroscience, 2020, 7(4): 438-458. doi: 10.3934/Neuroscience.2020027

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  • Major depressive disorder (MDD) is highly comorbid with anxiety disorders. It has been reported that the bed nucleus of the stria terminalis (BNST) is important for the induction of anxiety and MDD. Recently, the Gαq protein signaling within the BNST is involved in the induction of anxiety through Gαq protein signaling-mediated RNA-editing of GluR2 subunit, which produces the calcium (Ca2+)-impermeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor. On the other hand, the role of Gαq protein signaling within the BNST on the induction of MDD has never been reported yet. Therefore, we investigated whether Gαq protein signaling-producing the Ca2+-impermeable AMPA receptors in the BNST is involved in the lipopolysaccharide (LPS)-induced depressive-like behavior, particularly, despair-like behavior. When mice were systemically challenged with a single dose of LPS (1.2 mg/kg, i.p.), the immobility time during tail suspension test (TST) was increased 24 h after LPS injection. However, pretreatment with bilateral intra-BNST injection of neomycin (6.5 mM, 0.125 µL/side), an inhibitor of phospholipase C that is activated by Gαq protein-coupled receptor stimulation, extended the LPS-induced increase in the immobility time of TST. Furthermore, the co-pretreatment with bilateral intra-BNST injection of neomycin with 1-naphthylacetyl spermine (3 mM, 0.125 µL/side), an antagonist of Ca2+-permeable AMPA receptor, to mimic one of the final forms of Gαq protein activation, abolished the aggravated effect of neomycin and significantly shortened the immobility time compared with the control mice with an intra-BNST injection of artificial cerebrospinal fluid before LPS injection. However, pretreatment with bilateral intra-BNST injection of MDL-12,330A (10 µM, 0.125 µL/side), an inhibitor of adenylyl cyclase that is activated by Gαs protein-coupled receptor stimulation, did not affect the LPS-induced increase in the immobility time of TST. These results indicate that the Gαq protein signaling-mediated RNA-editing of GluR2, which produces the Ca2+-impermeable AMPA receptors within the BNST, regulates the LPS-induced despair-like behavior.


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    Abbreviation aCSF: artificial cerebrospinal fluid; ANOVA: analysis of variance; AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; BNST: bed nucleus of the stria terminalis; FST: forced swimming test; LTD: long-term depression; LPS: lipopolysaccharide; MDD: major depressive disorder; mGluR: metabotropic glutamate receptor; mPFC: medial prefrontal cortex; Naspm: 1-naphthylacetyl spermine; PBS: phosphate-buffered saline; PFA: paraformaldehyde; SNRI: serotonin and noradrenaline reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor; TST: tail suspension test; VTA: ventral tegmental area;
    Acknowledgment



    The authors thank Mr. Shisui Fujita, Mr. Masamitsu Masubuchi, and Mr. Ryuma Kamimura for their technical support. This work was partly supported by the Ministry of Health, Labor and Welfare, Japan, JSPS KAKENHI Grant Number JP19K06959 (K. Seki), and the research grant by the School of Pharmaceutical Science, Ohu University (K. Seki). The funding bodies did not play any role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

    Author contributions



    Nao Fukuwada and Miki Kanno performed experiments, acquisition, and analysis of all data. Satomi Yoshida designed the experiments, performed experiments and the analysis of all data. Kenjiro Seki conceived and designed the experiments and wrote the first draft of the manuscript. Nao Fukuwada, Miki Kanno, Satomi Yoshida and Kenjiro Seki analyzed and interpreted all data. All authors read and approved the final manuscript. Kenjiro Seki has to declare the contributions of individual authors when submitting the article, according to the ICMJE definitions.

    Conflict of interest



    The authors declare no conflict of interest.

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