Glial pathology in an animal model of depression: reversal of stress-induced cellular, metabolic and behavioral deficits by the glutamate-modulating drug riluzole

Abstract

Growing evidence indicates that glia pathology and amino-acid neurotransmitter system abnormalities contribute to the pathophysiology and possibly the pathogenesis of major depressive disorder. This study investigates changes in glial function occurring in the rat prefrontal cortex (PFC) after chronic unpredictable stress (CUS), a rodent model of depression. Furthermore, we analyzed the effects of riluzole, a Food and Drug Administration-approved drug for the treatment of amyotrophic laterosclerosis, known to modulate glutamate release and facilate glutamate uptake, on CUS-induced glial dysfunction and depressive-like behaviors. We provide the first experimental evidence that chronic stress impairs cortical glial function. Animals exposed to CUS and showing behavioral deficits in sucrose preference and active avoidance exhibited significant decreases in 13C-acetate metabolism reflecting glial cell metabolism, and glial fibrillary associated protein (GFAP) mRNA expression in the PFC. The cellular, metabolic and behavioral alterations induced by CUS were reversed and/or blocked by chronic treatment with the glutamate-modulating drug riluzole. The beneficial effects of riluzole on CUS-induced anhedonia and helplessness demonstrate the antidepressant action of riluzole in rodents. Riluzole treatment also reversed CUS-induced reductions in glial metabolism and GFAP mRNA expression. Our results are consistent with recent open-label clinical trials showing the drug's effect in mood and anxiety disorders. This study provides further validation of hypothesis that glial dysfunction and disrupted amino-acid neurotransmission contribute to the pathophysiology of depression and that modulation of glutamate metabolism, uptake and/or release represent viable targets for antidepressant drug development.

Increased Vulnerability to Depressive-Like Behavior of Mice with Decreased Expression of VGLUT1

“…We suggest that the downregulation of VGAT and its coupled GABA synthesising enzyme GAD65 in response to CMS could explain the decreased GABA levels observed in the frontal cortex and in the hippocampus of the CMS mice. In addition, a recent study addressing the effects of CMS on glial metabolism, has shown decreased glial GABA formation (49) which is consistent with our results. The upregulation of hippocampal EAAT1 may occur as a neuroprotective response to stressinduced elevations in glutamate in the synaptic cleft (32,33) as well as in response to increased corticosterone levels (50).…”

“…Moreover, mice lacking an isoform of GAD65 have shown reduced GABA levels and increased anxiety (46,47) while rats exposed to CMS show reduced GABA levels, anhedonia and helplessness (48,49). We suggest that the downregulation of VGAT and its coupled GABA synthesising enzyme GAD65 in response to CMS could explain the decreased GABA levels observed in the frontal cortex and in the hippocampus of the CMS mice.…”

Neuropharmacological and Neurobiological Relevance of In vivo 1H-MRS of GABA and Glutamate for Preclinical Drug Discovery in Mental Disorders

“…On the glutamatergic side, inhibition of the glutamine synthetase by MSO is known to result in a pronounced reduction of cerebral glutamate (Fonnum and Paulsen, 1990;Ghoddoussi et al, 2010). Likewise, riluzole is supposed to reduce neural glutamate levels by its polypharmacological action as suppressor of presynaptic vesicular glutamate release and enhancer of EAAT-mediated glutamate scavenging that together convey anticonvulsant and neuroprotective therapy (Banasr et al, 2010;Kim et al, 2007). Hence, our pharmacoMRS assessments have indeed faithfully reported these anticipated primary pharmacological effects of the latter prototypical GABAergic and glutamatergic interventions.…”

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

“…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). Reduced coupling between gap junctions of astroglial cells in prefrontal cortex associated with reduced expression of connexin-43 (gap junction) proteins leading to anhedonia following pharmacological inhibition of gap junctional conductance or chronic stress in laboratory animals (Sun et al, 2012).…”