RT Journal Article
SR Electronic
T1 Glial Dysfunction in the Mouse Habenula Causes Depressive-Like Behaviors and Sleep Disturbance
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 16273
OP 16285
DO 10.1523/JNEUROSCI.1465-14.2014
VO 34
IS 49
A1 Cui, Wanpeng
A1 Mizukami, Hiroaki
A1 Yanagisawa, Michiko
A1 Aida, Tomomi
A1 Nomura, Masatoshi
A1 Isomura, Yoshikazu
A1 Takayanagi, Ryoichi
A1 Ozawa, Keiya
A1 Tanaka, Kohichi
A1 Aizawa, Hidenori
YR 2014
UL http://www.jneurosci.org/content/34/49/16273.abstract
AB 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.