Glutamate toxicity in the striatum of the R6/2 Huntington's disease transgenic mice is age-dependent and correlates with decreased levels of glutamate transporters

Estrada‐Sánchez, Ana María; Montiel, Teresa; Segovia, José; Massieu, Lourdes

doi:10.1016/j.nbd.2008.12.017

Cited by 92 publications

(94 citation statements)

References 43 publications

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“…8D)] and, in particular, GLT-1 [F(3,31)=27.85; P<0.01 (Fig. 8C)], also in accordance with previous data [36], but, in this case, there was no recovery by the treatment with CBG (Fig. 8C, D).…”

Section: Study Of Neuroprotective Effects Of Cbg In R6/2 Micesupporting

confidence: 92%

Neuroprotective Properties of Cannabigerol in Huntington's Disease: Studies in R6/2 Mice and 3-Nitropropionate-lesioned Mice

Navarrete²,

et al. 2015

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Different plant-derived and synthetic cannabinoids have shown to be neuroprotective in experimental models of Huntington's disease (HD) through cannabinoid receptordependent and/or independent mechanisms. Herein, we studied the effects of cannabigerol (CBG), a nonpsychotropic phytocannabinoid, in 2 different in vivo models of HD. CBG was extremely active as neuroprotectant in mice intoxicated with 3-nitropropionate (3NP), improving motor deficits and preserving striatal neurons against 3NP toxicity. In addition, CBG attenuated the reactive microgliosis and the upregulation of proinflammatory markers induced by 3NP, and improved the levels of antioxidant defenses that were also significantly reduced by 3NP. We also investigated the neuroprotective properties of CBG in R6/2 mice. Treatment with this phytocannabinoid produced a much lower, but significant, recovery in the deteriorated rotarod performance typical of R6/2 mice. Using HD array analysis, we were able to identify a series of genes linked to this disease (e.g., symplekin, Sin3a, Rcor1, histone deacetylase 2, huntingtin-associated protein 1, δ subunit of the gamma-aminobutyric acid-A receptor (GABA-A), and hippocalcin), whose expression was altered in R6/2 mice but partially normalized by CBG treatment. We also observed a modest improvement in the gene expression for brain-derived neurotrophic factor (BDNF), insulinlike growth factor-1 (IGF-1), and peroxisome proliferatoractivated receptor-γ (PPARγ), which is altered in these mice, as well as a small, but significant, reduction in the aggregation of mutant huntingtin in the striatal parenchyma in CBGtreated animals. In conclusion, our results open new research avenues for the use of CBG, alone or in combination with other phytocannabinoids or therapies, for the treatment of neurodegenerative diseases such as HD.

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Section: Study Of Neuroprotective Effects Of Cbg In R6/2 Micesupporting

confidence: 92%

Neuroprotective Properties of Cannabigerol in Huntington's Disease: Studies in R6/2 Mice and 3-Nitropropionate-lesioned Mice

Navarrete²,

et al. 2015

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“…However, because of the fact that simultaneous depolarization and hyperpolarization are imbedded in the extracellular field potentials, the question remains whether the observed altered plasticity reflects excitatory inputs to striatal neurons or changes in inhibitory transmission within the striatum. An increased reactivity at prefrontal excitatory inputs may potentially favor glutamate excitotoxicity, a hypothesized mechanism for degenerative processes in HD (Olney et al, 1990;Zeron et al, 2002;Estrada-Sánchez et al, 2009). A change in striatal inhibitory control would affect the striatal output.…”

Section: Neurophysiological Assessment Of Presymptomatic Prefrontostrmentioning

confidence: 99%

Behavioral and In Vivo Electrophysiological Evidence for Presymptomatic Alteration of Prefrontostriatal Processing in the Transgenic Rat Model for Huntington Disease

Höhn¹,

Dallérac²,

Faure³

et al. 2011

Journal of Neuroscience

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Cognitive decline precedes motor symptoms in Huntington disease (HD). A transgenic rat model for HD carrying only 51 CAG repeats recapitulates the late-onset HD phenotype. Here, we assessed prefrontostriatal function in this model through both behavioral and electrophysiological assays. Behavioral examination consisted in a temporal bisection task within a supra-second range (2 vs.8 s), which is thought to involve prefrontostriatal networks. In two independent experiments, the behavioral analysis revealed poorer temporal sensitivity as early as 4 months of age, well before detection of overt motor deficits. At a later symptomatic age, animals were impaired in their temporal discriminative behavior. In vivo recording of field potentials in the dorsomedial striatum evoked by stimulation of the prelimbic cortex were studied in 4-to 5-month-old rats. Input/output curves, paired-pulse function, and plasticity induced by theta-burst stimulation (TBS) were assessed. Results showed an altered plasticity, with higher paired-pulse facilitation, enhanced short-term depression, as well as stronger long-term potentiation after TBS in homozygous transgenic rats. Results from the heterozygous animals mostly fell between wild-type and homozygous transgenic rats. Our results suggest that normal plasticity in prefrontostriatal circuits may be necessary for reliable and precise timing behavior. Furthermore, the present study provides the first behavioral and electrophysiological evidence of a presymptomatic alteration of prefrontostriatal processing in an animal model for Huntington disease and suggests that supra-second timing may be the earliest cognitive dysfunction in HD.

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“…This may be most relevant in Huntington's disease, as previous work has demonstrated impaired glutamate uptake in the prefrontal cortex of postmortem patients (Hassel et al 2008), which has also been shown to promote glutamate excitotoxicity in the R6/2 mouse model of Huntington's disease (Estrada-Sánchez et al 2009). In support of this, several studies have demonstrated reduced severity of motor deficits in the R6 mouse lines with chronic exercise training (van Dellen et al 2000;Pang et al 2006;Herbst and Holloway 2015b), and we have recently reported that exercise training is capable of partially normalizing changes to brain mitochondria in R6/1 mice (Herbst and Holloway 2015b).…”

Section: Discussionmentioning

confidence: 97%

Exercise increases mitochondrial glutamate oxidation in the mouse cerebral cortex

Herbst

Holloway

2016

Appl. Physiol. Nutr. Metab.

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The present study investigated the impact of acute exercise on stimulating mitochondrial respiratory function in mouse cerebral cortex. Where pyruvate-stimulated respiration was not affected by acute exercise, glutamate respiration was enhanced following the exercise bout. Additional assessment revealed that this affect was dependent on the presence of malate and did not occur when substituting glutamine for glutamate. As such, our results suggest that glutamate oxidation is enhanced with acute exercise through activation of the malate-aspartate shuttle.Key words: glutamate metabolism, exercise, brain mitochondria, cerebral cortex.Résumé : La présente étude examine l'impact d'un exercice ponctuel sur la stimulation de la fonction respiratoire des mitochondries dans le cortex cérébral d'une souris. La respiration stimulée par le pyruvate n'est pas touchée par l'exercice ponctuel alors que la respiration stimulée par le glutamate est améliorée à la suite de l'exercice ponctuel. Une évaluation supplémentaire révèle que l'effet dépend de la présence du malate et ne se produit pas quand on remplace la glutamine par le glutamate. Ainsi, nos résultats suggèrent que l'oxydation du glutamate est améliorée avec l'exercice ponctuel par l'activation de la navette malate-aspartate. [Traduit par la Rédaction]Mots-clés : métabolisme du glutamate, exercice physique, mitochondrie cérébrale, cortex cérébral.

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Glutamate toxicity in the striatum of the R6/2 Huntington's disease transgenic mice is age-dependent and correlates with decreased levels of glutamate transporters

Cited by 92 publications

References 43 publications

Neuroprotective Properties of Cannabigerol in Huntington's Disease: Studies in R6/2 Mice and 3-Nitropropionate-lesioned Mice

Neuroprotective Properties of Cannabigerol in Huntington's Disease: Studies in R6/2 Mice and 3-Nitropropionate-lesioned Mice

Behavioral and In Vivo Electrophysiological Evidence for Presymptomatic Alteration of Prefrontostriatal Processing in the Transgenic Rat Model for Huntington Disease

Exercise increases mitochondrial glutamate oxidation in the mouse cerebral cortex

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