Reduced expression of glutamate transporters vGluT1, EAAT2 and EAAT4 in learned helpless rats, an animal model of depression

Zink, Mathias; Vollmayr, Barbara; Gebicke‐Haerter, Peter J.; Henn, Fritz A.

doi:10.1016/j.neuropharm.2009.09.005

Cited by 156 publications

(130 citation statements)

References 76 publications

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“…Recent studies have reported reduced GLT-1 in patients with major depression (Choudary et al, 2005;Medina et al, 2013;Oh et al, 2014) and in rat models of depression (Zink et al, 2010), suggesting that reduced glial glutamate transport activity underlies depression. In support of this view, ceftriaxone, which enhances the transcriptional activity of GLT-1 (Rothstein et al, 2005), has antidepressant effects in animal models (Mineur et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Glial Dysfunction in the Mouse Habenula Causes Depressive-Like Behaviors and Sleep Disturbance

Cui¹,

Mizukami

Yanagisawa³

et al. 2014

J. Neurosci.

116

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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.

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Section: Discussionmentioning

confidence: 99%

Glial Dysfunction in the Mouse Habenula Causes Depressive-Like Behaviors and Sleep Disturbance

Cui¹,

Mizukami

Yanagisawa³

et al. 2014

J. Neurosci.

116

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“…Animals expressing learned helplessness showed a significantly suppressed expression of the glial glutamate transporter GLT1 (rodent nomenclature for EAAT2) in hippocampus and cerebral cortex compared with non-helpless animals and littermates with low levels of helplessness (Zink et al, 2010). Reduced glial fibrillary acidic protein (GFAP) expression is observed following chronic unpredictable stress (CUS) is associated with depressive-like behaviors in rodent models, and pharmacological treatments that attenuate the effects of CUS on of GFAP expression and/or facilitate EAAT function can reverse the cellular and behavioral effects of CUS (Banasr et al, 2010;Czeh et al, 2006;Gourley et al, 2012;Mineur et al, 2007;Sanacora and Banasr, 2013) Induction of anhedonia in laboratory animals by inhibition of astroglial surface (plasmalemmal) glutamate transporters (Bechtholt-Gompf et al, 2010;Ongur et al, 2014).…”

Section: Box 1 Examples Of Evidence Suggesting a Role For Astrocyte Pmentioning

confidence: 99%

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

Haroon

Miller

Sanacora

2016

Neuropsychopharmacol

383

299

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Increasing data indicate that inflammation and alterations in glutamate neurotransmission are two novel pathways to pathophysiology in mood disorders. The primary goal of this review is to illustrate how these two pathways may converge at the level of the glia to contribute to neuropsychiatric disease. We propose that a combination of failed clearance and exaggerated release of glutamate by glial cells during immune activation leads to glutamate increases and promotes aberrant extrasynaptic signaling through ionotropic and metabotropic glutamate receptors, ultimately resulting in synaptic dysfunction and loss. Furthermore, glutamate diffusion outside the synapse can lead to the loss of synaptic fidelity and specificity of neurotransmission, contributing to circuit dysfunction and behavioral pathology. This review examines the fundamental role of glia in the regulation of glutamate, followed by a description of the impact of inflammation on glial glutamate regulation at the cellular, molecular, and metabolic level. In addition, the role of these effects of inflammation on glia and glutamate in mood disorders will be discussed along with their translational implications.

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“…psychogenetically or pharmacogenetically selected rodent strains (e.g. [9,11,[17][18][19][20][21]), may provide "depresssion" models per se, without the need of using previous exposure to predisposing factors such as stressful experiences (see further in the "Discussion").…”

Section: Introductionmentioning

confidence: 99%

Helplessness-like escape deficits of NIH-HS rats predict passive behavior in the forced swimming test: Relevance for the concurrent validity of rat models of depression

Palència¹,

Díaz-Morán²,

Mont-Cardona³

et al. 2013

WJNS

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The genetically heterogeneous NIH-HS rat stock has been characterized by its response to anxiety-and fear-inducing situations, thus leading to the conclusion that they are a rather anxious and passive coping type of rats. Taking advantage of these profiles, and knowing that they show very poor performance in the two-way active (shuttle box) escape/avoidance task, we have tested NIH-HS rats (n = 80) in the forced swimming test (FST) as well as we have studied escape response deficits (i.e. response failures) of the same animals in the two-way shuttle box task. They were also tested for anxiety in the elevated zero-maze. The goal of such a study was that of investigating whether there are associations or relationships among helplessness-like or passive coping responses between both models of depression, i.e. the FST and the helplessness-like escape deficits in the shuttle box task. The results for the first time show associations among responses from both depression models and that selecting rats for displaying extreme (active or passive) responses in one of the models predict in a coherent manner (according to the hypothesis) their behaviour in the other model. These findings are discussed in the context of the concurrent validity of both models of depression as well as concerning the possible relevance of NIH-HS rats as a tool for future studies on this field.

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Reduced expression of glutamate transporters vGluT1, EAAT2 and EAAT4 in learned helpless rats, an animal model of depression

Cited by 156 publications

References 76 publications

Glial Dysfunction in the Mouse Habenula Causes Depressive-Like Behaviors and Sleep Disturbance

Glial Dysfunction in the Mouse Habenula Causes Depressive-Like Behaviors and Sleep Disturbance

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

Helplessness-like escape deficits of NIH-HS rats predict passive behavior in the forced swimming test: Relevance for the concurrent validity of rat models of depression

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