G protein-activated inwardly rectifying K+ channel inhibition and rescue of weaver mouse motor functions by antidepressants
Abstract
Antidepressants, including tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs), have been widely used for the treatment of not only depression but also other psychiatric disorders, although the molecular mechanisms of the drug effects have not yet been sufficiently revealed. Here, we investigated the in vivo effects of these antidepressants on G protein-activated inwardly rectifying K+ (GIRK) channels, which are important for regulating the excitability of various cells, by using weaver (wv) mice, which have mutant GIRK channels and show abnormal neuronal cell death and motor disturbances. First, we found that a widely used SSRI fluoxetine (also known as Prozac) effectively inhibited wv GIRK2 channels like wild-type GIRK channels, expressed in Xenopus oocytes. Next, we found that weaver motor disturbances were remarkably alleviated by chronic treatment with fluoxetine or desipramine. Furthermore, the chronic fluoxetine treatment substantially suppressed the abnormal neuronal cell death in the weaver mouse cerebellum and pontine nuclei. These results suggest that continuous inhibition of wv GIRK2 channels by a group of antidepressants caused substantial suppression of the neuronal cell death and resulted in improvement of motor abilities in weaver mice. These results provide evidence for in vivo GIRK channel inhibition by a group of antidepressants.
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Serotonergic drugs are among the most widely prescribed medications for individuals with autism, and while not specifically studied in autism for cerebellar effects, fluoxetine rescues some aspects of the consequences of neuronal cell death in the cerebellum in the Weaver mouse via effects on GIRK2 channels.
“Serotonergic drugs are among the most widely prescribed medications for individuals with autism, and while not specifically studied in autism for their cerebellar effects, it is interesting that the SSRI, fluoxetine, rescues some aspects of the consequences of neuronal cell death in the cerebellum in the Weaver mouse via its effects on GIRK2 channels [260].”
From Consensus Paper: Pathological Role of the Cerebellum in Autism (2012) · cites this paper as [260]
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Consensus Paper: Pathological Role of the Cerebellum in Autism
Fatemi, S. H., Aldinger, K. A., Ashwood, P., Bauman, M. L., Blaha, C. D., Blatt, G. J., Chauhan, A., Chauhan, V., Dager, S. R., Dickson, P. E., et al. (2012) · The Cerebellum · doi:10.1007/s12311-012-0355-9 · Cited by 723 · see citing works
- Authors
- Takahashi, T., Kobayashi, T., Ozaki, M., Takamatsu, Y., Ogai, Y., Ohta, M., Yamamoto, H., & Ikeda, K.
- Affiliations
- Tokyo Institute of Psychiatry (JP)
- Brain Research Institute, Niigata University (JP)
- Waseda University (JP)
- Azabu University (JP)
- Corresponding author
- Ikeda, Kazutaka
- Venue
- Neuroscience Research
- Publisher
- Elsevier BV
- Published
- 2006-02
- Volume
- 54
- Issue
- 2
- Pages
- 104-111
- ISSN
- 0168-0102 (ISSN-L)
- OpenAlex
- W2063366770
- Cited by
- 22
- References
- 42
- Citations by year
- 2026: 1 · 2024: 1 · 2021: 2 · 2017: 1 · 2015: 1 · 2014: 1 · 2012: 1
- FWCI
- 0.63
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuroscience Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology (17025054)
- Ministry of Health, Labour and Welfare (15-kou-3-03, H14-toxico-011, H16-iyaku-029, H17-pharmaco-001)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- GIRK2, weaver mouse, antidepressants, fluoxetine, desipramine, selective serotonin reuptake inhibitors, tricyclic antidepressants, neuronal cell death, motor function, cerebellum, pontine nuclei, channel inhibition
- MeSH terms
- Animals, Antidepressive Agents, Antidepressive Agents, Tricyclic, Behavior, Animal, Desipramine, Fluoxetine, Mice, Inbred C3H, Mice, Neurologic Mutants, Movement Disorders, Oocytes, RNA, Messenger, Xenopus, Cell Death, Antidepressive Agents, Second-Generation, GTP-Binding Proteins, Potassium Channels, Inwardly Rectifying, Potassium Channel Blockers, Mice, G Protein-Coupled Inwardly-Rectifying Potassium Channels
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