Role of phospholipase Cη1 in lateral habenula astrocytes in depressive-like behavior in mice
Abstract Phospholipase C (PLC) enzymes play crucial roles in intracellular calcium-signaling transduction. Several brain PLC subtypes have been extensively studied, implicating them in psychiatric disorders such as depression, epilepsy and schizophrenia. However, the role of the recently identified...
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Nature Publishing Group
2025-04-01
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| Series: | Experimental and Molecular Medicine |
| Online Access: | https://doi.org/10.1038/s12276-025-01432-1 |
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| author | Sukwoon Song Miseon Kang Jiyoung Lee Yong Ryoul Yang Ho Lee Jae-Ick Kim Beomsue Kim Hoon-seong Choi Eun-bin Hong Min-ho Nam Pann-Ghill Suh Jeongyeon Kim |
| author_facet | Sukwoon Song Miseon Kang Jiyoung Lee Yong Ryoul Yang Ho Lee Jae-Ick Kim Beomsue Kim Hoon-seong Choi Eun-bin Hong Min-ho Nam Pann-Ghill Suh Jeongyeon Kim |
| author_sort | Sukwoon Song |
| collection | DOAJ |
| description | Abstract Phospholipase C (PLC) enzymes play crucial roles in intracellular calcium-signaling transduction. Several brain PLC subtypes have been extensively studied, implicating them in psychiatric disorders such as depression, epilepsy and schizophrenia. However, the role of the recently identified PLCη remains largely unknown. We found that PLCη1 is prominently expressed in lateral habenula (LHb) astrocytes. Here, to investigate its physiological role, we generated astrocyte-specific PLCη1 conditional knockout (cKO) mice (Plch1 f/f ; Aldh1l1-Cre ERT2 ). In these cKO mice, we observed a reduction in cellular morphological complexity metrics, such as total process length, as well as a decrease in the passive membrane conductance of LHb astrocytes. Additionally, neuronal function was impacted by the cKO, as the synaptic efficacy and firing rates of LHb neurons increased, while extrasynaptic long-term depression was impaired. Both tonic α-amino-3-hydroxy-5-methyl-4-isoxazolepdlropionic acid receptor/N-methyl-d-aspartate receptor (AMPAR/NMDAR) currents and extracellular glutamate levels were reduced. Interestingly, chemogenetic activation of astrocytes restored the reduced tonic AMPAR/NMDAR currents in cKO mice. Furthermore, LHb astrocyte-specific deletion of PLCη1 via AAV-GFAP-Cre injection induced depressive-like behaviors in mice, which were reversed by chemogenetic activation of LHb astrocytes. Finally, we found that restraint stress exposure decreased Plch1 mRNA expression in the LHb. These findings suggest that PLCη1 could be a potential therapeutic target for depression and highlight the critical role of astrocytes in the etiology of neuropsychiatric disorders. |
| format | Article |
| id | doaj-art-6ea484954aae4759bc99f0507a44bb29 |
| institution | DOAJ |
| issn | 2092-6413 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Experimental and Molecular Medicine |
| spelling | doaj-art-6ea484954aae4759bc99f0507a44bb292025-08-20T02:55:21ZengNature Publishing GroupExperimental and Molecular Medicine2092-64132025-04-0157487288710.1038/s12276-025-01432-1Role of phospholipase Cη1 in lateral habenula astrocytes in depressive-like behavior in miceSukwoon Song0Miseon Kang1Jiyoung Lee2Yong Ryoul Yang3Ho Lee4Jae-Ick Kim5Beomsue Kim6Hoon-seong Choi7Eun-bin Hong8Min-ho Nam9Pann-Ghill Suh10Jeongyeon Kim11Emotion, Cognition and Behavior Research Group, Korea Brain Research InstituteEmotion, Cognition and Behavior Research Group, Korea Brain Research InstituteEmotion, Cognition and Behavior Research Group, Korea Brain Research InstituteAging Convergence Research Center, Korea Research Institute of Bioscience and BiotechnologyCancer Experimental Resources Branch, National Cancer CenterDepartment of Biological Sciences, Ulsan National Institute of Science and TechnologyNeural Circuits Research Group, Korea Brain Research InstituteResearch Animal Resource Center, Korea Institute of Science and TechnologyBrain Science Institute, Korea Institute of Science and TechnologyBrain Science Institute, Korea Institute of Science and TechnologyKorea Brain Research InstituteEmotion, Cognition and Behavior Research Group, Korea Brain Research InstituteAbstract Phospholipase C (PLC) enzymes play crucial roles in intracellular calcium-signaling transduction. Several brain PLC subtypes have been extensively studied, implicating them in psychiatric disorders such as depression, epilepsy and schizophrenia. However, the role of the recently identified PLCη remains largely unknown. We found that PLCη1 is prominently expressed in lateral habenula (LHb) astrocytes. Here, to investigate its physiological role, we generated astrocyte-specific PLCη1 conditional knockout (cKO) mice (Plch1 f/f ; Aldh1l1-Cre ERT2 ). In these cKO mice, we observed a reduction in cellular morphological complexity metrics, such as total process length, as well as a decrease in the passive membrane conductance of LHb astrocytes. Additionally, neuronal function was impacted by the cKO, as the synaptic efficacy and firing rates of LHb neurons increased, while extrasynaptic long-term depression was impaired. Both tonic α-amino-3-hydroxy-5-methyl-4-isoxazolepdlropionic acid receptor/N-methyl-d-aspartate receptor (AMPAR/NMDAR) currents and extracellular glutamate levels were reduced. Interestingly, chemogenetic activation of astrocytes restored the reduced tonic AMPAR/NMDAR currents in cKO mice. Furthermore, LHb astrocyte-specific deletion of PLCη1 via AAV-GFAP-Cre injection induced depressive-like behaviors in mice, which were reversed by chemogenetic activation of LHb astrocytes. Finally, we found that restraint stress exposure decreased Plch1 mRNA expression in the LHb. These findings suggest that PLCη1 could be a potential therapeutic target for depression and highlight the critical role of astrocytes in the etiology of neuropsychiatric disorders.https://doi.org/10.1038/s12276-025-01432-1 |
| spellingShingle | Sukwoon Song Miseon Kang Jiyoung Lee Yong Ryoul Yang Ho Lee Jae-Ick Kim Beomsue Kim Hoon-seong Choi Eun-bin Hong Min-ho Nam Pann-Ghill Suh Jeongyeon Kim Role of phospholipase Cη1 in lateral habenula astrocytes in depressive-like behavior in mice Experimental and Molecular Medicine |
| title | Role of phospholipase Cη1 in lateral habenula astrocytes in depressive-like behavior in mice |
| title_full | Role of phospholipase Cη1 in lateral habenula astrocytes in depressive-like behavior in mice |
| title_fullStr | Role of phospholipase Cη1 in lateral habenula astrocytes in depressive-like behavior in mice |
| title_full_unstemmed | Role of phospholipase Cη1 in lateral habenula astrocytes in depressive-like behavior in mice |
| title_short | Role of phospholipase Cη1 in lateral habenula astrocytes in depressive-like behavior in mice |
| title_sort | role of phospholipase cη1 in lateral habenula astrocytes in depressive like behavior in mice |
| url | https://doi.org/10.1038/s12276-025-01432-1 |
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