Glial dysfunction in the mouse habenula causes depressive-like behaviors and sleep disturbance

Wanpeng Cui, Hiroaki Mizukami, Michiko Yanagisawa, Tomomi Aida, Masatoshi Nomura, Yoshikazu Isomura, Ryoichi Takayanagi, Keiya Ozawa, Kohichi Tanaka, Hidenori Aizawa

Research output: Contribution to journalArticle

56 Citations (Scopus)

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 depressivelike 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 openfield 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.

Original languageEnglish
Pages (from-to)16273-16285
Number of pages13
JournalJournal of Neuroscience
Volume34
Issue number49
DOIs
Publication statusPublished - Dec 3 2014

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Habenula
Neuroglia
Sleep
Depression
Neurons
Astrocytes
Glutamic Acid
Hindlimb Suspension
Phenotype
Amino Acid Transport System X-AG
REM Sleep
Locomotion
Brain Stem
Psychiatry
Motivation
Animal Models
Pharmacology

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Cite this

Cui, W., Mizukami, H., Yanagisawa, M., Aida, T., Nomura, M., Isomura, Y., ... Aizawa, H. (2014). Glial dysfunction in the mouse habenula causes depressive-like behaviors and sleep disturbance. Journal of Neuroscience, 34(49), 16273-16285. https://doi.org/10.1523/JNEUROSCI.1465-14.2014

Glial dysfunction in the mouse habenula causes depressive-like behaviors and sleep disturbance. / Cui, Wanpeng; Mizukami, Hiroaki; Yanagisawa, Michiko; Aida, Tomomi; Nomura, Masatoshi; Isomura, Yoshikazu; Takayanagi, Ryoichi; Ozawa, Keiya; Tanaka, Kohichi; Aizawa, Hidenori.

In: Journal of Neuroscience, Vol. 34, No. 49, 03.12.2014, p. 16273-16285.

Research output: Contribution to journalArticle

Cui, W, Mizukami, H, Yanagisawa, M, Aida, T, Nomura, M, Isomura, Y, Takayanagi, R, Ozawa, K, Tanaka, K & Aizawa, H 2014, 'Glial dysfunction in the mouse habenula causes depressive-like behaviors and sleep disturbance', Journal of Neuroscience, vol. 34, no. 49, pp. 16273-16285. https://doi.org/10.1523/JNEUROSCI.1465-14.2014
Cui, Wanpeng ; Mizukami, Hiroaki ; Yanagisawa, Michiko ; Aida, Tomomi ; Nomura, Masatoshi ; Isomura, Yoshikazu ; Takayanagi, Ryoichi ; Ozawa, Keiya ; Tanaka, Kohichi ; Aizawa, Hidenori. / Glial dysfunction in the mouse habenula causes depressive-like behaviors and sleep disturbance. In: Journal of Neuroscience. 2014 ; Vol. 34, No. 49. pp. 16273-16285.
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