title: Glial dysfunction in the mouse habenula causes depressive-like behaviors and sleep disturbance.
abstract: 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.
authors.affiliation: Laboratory of Molecular Neuroscience, Medical Research Institute and.
authors.forename: Wanpeng
authors.initials: W
authors.lastname: Cui
authors.affiliation: Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, 329-0498 Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mizukami
authors.affiliation: Laboratory of Molecular Neuroscience, Medical Research Institute and.
authors.forename: Michiko
authors.initials: M
authors.lastname: Yanagisawa
authors.affiliation: Laboratory of Molecular Neuroscience, Medical Research Institute and.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Aida
authors.affiliation: Department of Medicine and Bioregulatory Science, Graduate School of Medical Science, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Nomura
authors.affiliation: Tamagawa University Brain Science Institute, 6-1-1 Tamagawa Gakuen, Machida, Tokyo, 194-8610 Japan, and.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Isomura
authors.affiliation: Department of Medicine and Bioregulatory Science, Graduate School of Medical Science, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Takayanagi
authors.affiliation: Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, 329-0498 Japan.
authors.forename: Keiya
authors.initials: K
authors.lastname: Ozawa
authors.affiliation: Laboratory of Molecular Neuroscience, Medical Research Institute and Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Sanbancho Building 5, Sanbancho, Chiyoda-ku, Tokyo 102-0075, Japan Center for Brain Integration Research, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510 Japan, haizawa.aud@mri.tmd.ac.jp tanaka.aud@mri.tmd.ac.jp.
authors.forename: Kohichi
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: Laboratory of Molecular Neuroscience, Medical Research Institute and haizawa.aud@mri.tmd.ac.jp tanaka.aud@mri.tmd.ac.jp.
authors.forename: Hidenori
authors.identifier: http://orcid.org/0000-0002-2896-1298
authors.initials: H
authors.lastname: Aizawa
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology*; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D003863:Depression / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D027342:Excitatory Amino Acid Transporter 2 / Q000037:antagonists & inhibitors / Q000235:genetics; D019262:Habenula / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D008845:Microinjections; D009474:Neurons / Q000502:physiology; D014179:Neurotransmitter Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D011753:Pyrones / Q000008:administration & dosage / Q000494:pharmacology; D012895:Sleep, REM / Q000235:genetics
chemical_list: D027342:Excitatory Amino Acid Transporter 2; D014179:Neurotransmitter Uptake Inhibitors; D011753:Pyrones; C113859:dihydrokavain
keywords: astrocytes; depression; glutamate transporters; habenula; monoamines; rapid eye movement sleep