Control of motor coordination by transient receptor potential melastatin 8 through γ-aminobutyric acidergic circuit modulation in the male mouse cerebellum
Abstract Transient receptor potential melastatin 8 (TRPM8) is a non-selective cation channel that is activated by mild cooling and chemical agents. Although TRPM8 is widely expressed in the peripheral and central nervous systems, its cerebellar distribution and functional significance remain unexplo...
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Nature Portfolio
2025-07-01
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| Online Access: | https://doi.org/10.1038/s41598-025-98837-9 |
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| author | Mayuka Koyama Koki Harada Naoko Takizawa Shinji Kobuchi Miwa Kambara Hikaru Tanaka Riona Araki Yuri Yamada Yukako Ito Kazuyuki Takata Shinichi Kato Kenjiro Matsumoto |
| author_facet | Mayuka Koyama Koki Harada Naoko Takizawa Shinji Kobuchi Miwa Kambara Hikaru Tanaka Riona Araki Yuri Yamada Yukako Ito Kazuyuki Takata Shinichi Kato Kenjiro Matsumoto |
| author_sort | Mayuka Koyama |
| collection | DOAJ |
| description | Abstract Transient receptor potential melastatin 8 (TRPM8) is a non-selective cation channel that is activated by mild cooling and chemical agents. Although TRPM8 is widely expressed in the peripheral and central nervous systems, its cerebellar distribution and functional significance remain unexplored. We investigated the expression and role of TRPM8 in motor function using TRPM8-enhanced green fluorescent protein and TRPM8-deficient (TRPM8KO) mice. TRPM8 immunoreactivity was observed in parvalbumin- and vesicular γ-aminobutyric acid (GABA) transporter-labeled interneurons. TRPM8 was also expressed in hyperpolarization-activated cyclic nucleotide-gated potassium channel 1-labeled inhibitory plexuses that enveloped GABAA receptor-expressing Purkinje cell somata and terminated as pinceau. Next, motor functions were assessed in wild-type and TRPM8KO mice. TRPM8KO mice exhibited abnormal motor coordination in the rotarod test. However, TRPM8 deficiency did not affect body balance in the footprint test or general spontaneous activity in the open field test. To explore the importance of TRPM8 in motor coordination, the TRPM8 antagonist RQ-00203078 or vehicle (control) was intracerebrally or intraperitoneally administered; motor responses were analyzed using the rotarod test. Compared with vehicle, RQ-00203078 significantly reduced the rotarod retention time. Our results suggest that TRPM8 channels on inhibitory GABAergic neurons contribute to motor coordination by modulating synaptic transmission in Purkinje cell–interneuron synapses. |
| format | Article |
| id | doaj-art-10d618eb8d6d48cfbebbf0e1f59f720f |
| institution | DOAJ |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-10d618eb8d6d48cfbebbf0e1f59f720f2025-08-20T03:03:36ZengNature PortfolioScientific Reports2045-23222025-07-0115111310.1038/s41598-025-98837-9Control of motor coordination by transient receptor potential melastatin 8 through γ-aminobutyric acidergic circuit modulation in the male mouse cerebellumMayuka Koyama0Koki Harada1Naoko Takizawa2Shinji Kobuchi3Miwa Kambara4Hikaru Tanaka5Riona Araki6Yuri Yamada7Yukako Ito8Kazuyuki Takata9Shinichi Kato10Kenjiro Matsumoto11Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical UniversityJoint Research Laboratory, Division of Integrated Pharmaceutical Sciences, Kyoto Pharmaceutical UniversityDivision of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical UniversityDepartment of Pharmacokinetics, Kyoto Pharmaceutical UniversityLaboratory of Pathophysiology, Faculty of Pharmaceutical Sciences, Doshisha Women’s College of Liberal ArtsDivision of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical UniversityJoint Research Laboratory, Division of Integrated Pharmaceutical Sciences, Kyoto Pharmaceutical UniversityJoint Research Laboratory, Division of Integrated Pharmaceutical Sciences, Kyoto Pharmaceutical UniversityDepartment of Pharmacokinetics, Kyoto Pharmaceutical UniversityJoint Research Laboratory, Division of Integrated Pharmaceutical Sciences, Kyoto Pharmaceutical UniversityDivision of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical UniversityDivision of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical UniversityAbstract Transient receptor potential melastatin 8 (TRPM8) is a non-selective cation channel that is activated by mild cooling and chemical agents. Although TRPM8 is widely expressed in the peripheral and central nervous systems, its cerebellar distribution and functional significance remain unexplored. We investigated the expression and role of TRPM8 in motor function using TRPM8-enhanced green fluorescent protein and TRPM8-deficient (TRPM8KO) mice. TRPM8 immunoreactivity was observed in parvalbumin- and vesicular γ-aminobutyric acid (GABA) transporter-labeled interneurons. TRPM8 was also expressed in hyperpolarization-activated cyclic nucleotide-gated potassium channel 1-labeled inhibitory plexuses that enveloped GABAA receptor-expressing Purkinje cell somata and terminated as pinceau. Next, motor functions were assessed in wild-type and TRPM8KO mice. TRPM8KO mice exhibited abnormal motor coordination in the rotarod test. However, TRPM8 deficiency did not affect body balance in the footprint test or general spontaneous activity in the open field test. To explore the importance of TRPM8 in motor coordination, the TRPM8 antagonist RQ-00203078 or vehicle (control) was intracerebrally or intraperitoneally administered; motor responses were analyzed using the rotarod test. Compared with vehicle, RQ-00203078 significantly reduced the rotarod retention time. Our results suggest that TRPM8 channels on inhibitory GABAergic neurons contribute to motor coordination by modulating synaptic transmission in Purkinje cell–interneuron synapses.https://doi.org/10.1038/s41598-025-98837-9CerebellumTransient receptor potential melastatin 8InterneuronGABAMotor coordinationRotarod test |
| spellingShingle | Mayuka Koyama Koki Harada Naoko Takizawa Shinji Kobuchi Miwa Kambara Hikaru Tanaka Riona Araki Yuri Yamada Yukako Ito Kazuyuki Takata Shinichi Kato Kenjiro Matsumoto Control of motor coordination by transient receptor potential melastatin 8 through γ-aminobutyric acidergic circuit modulation in the male mouse cerebellum Scientific Reports Cerebellum Transient receptor potential melastatin 8 Interneuron GABA Motor coordination Rotarod test |
| title | Control of motor coordination by transient receptor potential melastatin 8 through γ-aminobutyric acidergic circuit modulation in the male mouse cerebellum |
| title_full | Control of motor coordination by transient receptor potential melastatin 8 through γ-aminobutyric acidergic circuit modulation in the male mouse cerebellum |
| title_fullStr | Control of motor coordination by transient receptor potential melastatin 8 through γ-aminobutyric acidergic circuit modulation in the male mouse cerebellum |
| title_full_unstemmed | Control of motor coordination by transient receptor potential melastatin 8 through γ-aminobutyric acidergic circuit modulation in the male mouse cerebellum |
| title_short | Control of motor coordination by transient receptor potential melastatin 8 through γ-aminobutyric acidergic circuit modulation in the male mouse cerebellum |
| title_sort | control of motor coordination by transient receptor potential melastatin 8 through γ aminobutyric acidergic circuit modulation in the male mouse cerebellum |
| topic | Cerebellum Transient receptor potential melastatin 8 Interneuron GABA Motor coordination Rotarod test |
| url | https://doi.org/10.1038/s41598-025-98837-9 |
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