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Glial Dysfunction in the Mouse Habenula Causes Depressive-Like Behaviors and Sleep Disturbance
Open accessAbstract
The lateral habenula (LHb) regulates the activity of monoaminergic neurons in the brainstem. This area has recently attracted a surge of interest in psychiatry because studies have reported the pathological activation of the habenula in patients with major depression and in animal models. The LHb plays a significant role in the pathophysiology of depression; however, how habenular neurons are activated to cause various depression symptoms, such as reduced motivation and sleep disturbance, remain unclear. We hypothesized that dysfunctional astrocytes may cause LHb hyperactivity due to the defective uptake activity of extracellular glutamate, which induces depressive-like behaviors. We examined the activity of neurons in habenular pathways and performed behavioral and sleep analyses in mice with pharmacological and genetic inhibition of the activity of the glial glutamate transporter GLT-1 in the LHb. The habenula-specific inhibition of GLT-1 increased the neuronal firing rate and the level of c-Fos expression in the LHb. Mice with reduced GLT-1 activity in the habenula exhibited a depressive-like phenotype in the tail suspension and novelty-suppressed feeding tests. These animals also displayed increased susceptibility to chronic stress, displaying more frequent avoidant behavior without affecting locomotor activity in the open-field test. Intriguingly, the mice showed disinhibition of rapid eye movement sleep, which is a characteristic sleep pattern in patients with depression. These results provide evidence that disrupting glutamate clearance in habenular astrocytes increases neuronal excitability and depressive-like phenotypes in behaviors and sleep.
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“As glutamate clearance modulates neuronal excitability [200] and glutamatergic synapse strength contributes to depression [202], how astrocytic glutamate clearance contributes to excitatory synapse strength and subsequent depressive behavior is also worth further investigation in the reward circuit.”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [200]
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“Mice with reduced glutamate transporter GLT-1 expression in habenular astrocytes are more stress-susceptible and exhibit increased tail-suspension immobility at baseline [200], in agreement with reduced glutamate transporter expression in learned helpless rats [201].”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [200]
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Metadata
- Authors
- Cui, W., Mizukami, H., Yanagisawa, M., Aida, T., Nomura, M., Isomura, Y., Takayanagi, R., Ozawa, K., Tanaka, K., & Aizawa, H.
- Affiliations
- Jichi Medical University (JP)
- Kyushu University (JP)
- Tamagawa University (JP)
- Tokyo Medical and Dental University (JP)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2014-12-03
- Volume
- 34
- Issue
- 49
- Pages
- 16273-16285
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6608483
- OpenAlex
- W2052808411
- Cited by
- 139
- References
- 84
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 8 · 2023: 7 · 2022: 10 · 2021: 13 · 2020: 16 · 2019: 19 · 2018: 12 · 2017: 18 · 2016: 9 · 2015: 11
- FWCI
- 9.23
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Naito Foundation
- Suzuken Memorial Foundation
- Uehara Memorial Foundation
- Brain Science Foundation
- Ministry of Education, Culture, Sports, Science and Technology
- Inamori Foundation
- Kanae Foundation for the Promotion of Medical Science
- Japan Society for the Promotion of Science (24390247, 26430008)
- Japan Science and Technology Agency
- Core Research for Evolutional Science and Technology
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- lateral habenula, glial dysfunction, astrocytes, GLT-1, glutamate uptake, major depressive disorder, depression-like behavior, sleep disorders, chronic stress, neuronal excitability, c-fos
- MeSH terms
- Action Potentials, Animals, Astrocytes, Behavior, Animal, Depression, Mice, Transgenic, Microinjections, Neurons, Pyrones, Sleep, REM, Neurotransmitter Uptake Inhibitors, Habenula, Excitatory Amino Acid Transporter 2, Mice
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