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. 2010 May;15(5):501-11.
doi: 10.1038/mp.2008.106. Epub 2008 Sep 30.

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

M Banasr  1 , G M I Chowdhury, R Terwilliger, S S Newton, R S Duman, K L Behar, G Sanacora
Affiliations

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

M Banasr et al. Mol Psychiatry. 2010 May.

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.

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Figures

Figure 1
Figure 1
Timeline of experimental procedures. Rats are handled daily (home cage control, CTR) or subjected to the chronic unpredictable stress (CUS) procedure for 35 days. Animals are administered saline or riluzole (4 mg/kg) for the 21 last days of the experiment. The efficacy of CUS or riluzole on behavioral performances of the animals in locomotor activity, active avoidance and sucrose preferences test are measured.
Figure 2
Figure 2
Effects of chronic unpredictable stress (CUS) and riluzole in the sucrose preference test. (a) On day 15, CUS animals showed a significant decrease in sucrose preference when compared to home cage control (CTR) animals (t30 = 2.36, P = 0.025). (b) Sucrose preference was decreased by 35 days CUS exposure (F1,28 = 3.42, P < 0.01) and was reversed by chronic riluzole treatment (F1,28 = 5.258, P < 0.05). Error bars represent s.e.m. *P < 0.05, **P < 0.01 compared to CTR and #P < 0.05 compared to CUS, two-way analysis of the variance (ANOVA), Student–Newman–Keuls post hoc analysis.
Figure 3
Figure 3
Effects of chronic unpredictable stress (CUS) and riluzole in the active avoidance test. (a) CUS animals showed a significant increase of escape failures (F1,28 = 7.798, P < 0.01) and this effect was reversed by chronic riluzole treatment (F1,28 = 19.05, P < 0.001). Error bars represent s.e.m. **P < 0.01 compared to home cage control (CTR) and ##P < 0.01 compared to CUS, two-way analysis of the variance (ANOVA) and Student–Newman–Keuls post hoc analysis. (b) Latency to escape was significantly increased in CUS animals (F1,28 = 7.79, P < 0.01) starting from the second FR-2 block of five escapable shocks (footshocks 10–15) to the end of the test (F1,168 = 27.37, P < 0.01). Riluzole-treated animals showed performances in this test significantly different from CUS (F1,28 = 16.45, P < 0.01) as soon as the first FR-2 block of five escapable shocks (F1,168 = 45.57, P < 0.01). Error bars represent s.e.m. **P < 0.01 compared to CTR and ##P < 0.01 compared to CUS, Two-way repeated-measures ANOVA followed by Dunnett's post hoc analysis.
Figure 4
Figure 4
Effects of chronic unpredictable stress (CUS) and riluzole on 13C concentrations and -enrichment of Glu-C4, Gln-C4 and GABA-C2 after 13C-acetate infusion. (a) Schematic depiction of the major metabolic pathways of 13C isotopic label flow from the astroglial substrate, [2-13C]acetate. After transport into the brain from blood, [2-13C]acetate is metabolized in the mitochondria to acetyl-CoA (labeled at C2, Ac2CoA) and enters the astroglial TCA cycle (TCAa) as citrate labeled at C4 after condensation with oxaloacetate (oaa). Further metabolism along the cycle labels α-ketoglutarate (α-KG) at C4, which can then exchange with the astroglial glutamate pool (small pool glutamate) transferring 13C label to C4 (Glu4). With time the 13C label traverses the complete TCA cycle, labeling the other carbon positions, e.g., C3, C2, C1. The initial rate of label trapping at Gln4 is related to astroglial TCA cycle flux, whereas Glu4 and Gaba2 are related to the glutamate/GABA/glutamine cycle fluxes. Astroglia precursors (mainly Gln4) are released from the astroglia, transferring the label to neurons for synthesis of Glu4 and Gaba2. Only flux pathways labeling Gln4, Glu4, Gaba2 from [2-13C] acetate are shown. The pyruvate carboxylation pathway (anaplerosis) in astroglia is depicted by the dashed arrow. The continuous metabolism of unlabeled glucose in neurons and astroglia through pyruvate dehydrogenase (pyr → acetyl-CoA) serves as a constant dilution flux. Definitions: (subscripts) a, astroglia; n, neuron; acetyl-CoA, acetyl-coenzyme A; suc, succinate; TCAn, neuronal TCA cycle. (b) 13C concentration of Glu-C4 was significantly decreased by CUS (F1,28 = 2.79, P < 0.05) and this effect was reversed by riluzole treatment (F1,28 = 7.8, P < 0.05). (c) CUS significantly reduced 13C concentration of Gln-C4 (F1,28 = 13.71, P < 0.001) and riluzole did not significantly reverse this effect. (d) 13C concentration of GABA-C2 was significantly decreased by CUS (F1,28 = 4.63, P < 0.05) and this effect was reversed by riluzole treatment (F1,28 = 5.39, P < 0.01).
Figure 5
Figure 5
Effects of chronic unpredictable stress (CUS) and riluzole on mRNA levels of glial-specific markers. (a) CUS showed a significant decrease of mRNA levels of glial fibrillary associated protein (GFAP) compared to home cage control (CTR) animals (F1,16 = 4.52, P < 0.05). CUS animals treated with riluzole were significantly different from CUS animals treated with saline and not different from CTR animals treated with saline or riluzole (F1,16 = 5.7, P < 0.05). Representative autograph of effect of CUS (c) on GFAP mRNA expression compared to CTR (b). (d) Although CUS has no effect on mRNA level of GLT-1, chronic riluzole treatment significantly increased GLT-1 transcript (F1,16 = 4.9, P < 0.05). Representative autograph of effect of CUS (e) on GLT-1 mRNA expression compared to a CUS animal treated with riluzole (f). Error bars represent s.e.m. *P < 0.05 compared to CTR and #P < 0.05 compared to CUS, two-way analysis of the variance (ANOVA), Student–Newman–Keuls post hoc analysis.
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