Disturbance of the glutamatergic system by glutaric acid in striatum and cerebral cortex of glutaryl-CoA dehydrogenase-deficient knockout mice: Possible implications for the neuropathology of glutaric acidemia type I

Busanello, Estela Natacha Brandt; Fernandes, Carolina Gonçalves; Martell, R.; Lobato, Vannessa Gonçalves Araujo; Goodman, Stephen I.; Woontner, Michael; Souza, Diogo O.; Wajner, Moaçir

doi:10.1016/j.jns.2014.09.003

Cited by 13 publications

(9 citation statements)

References 54 publications

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“…Finally, overexpression of all glutamate ionotropic receptors was demonstrated in cerebral cortex and striatum of adult (60‐day‐old) Gcdh −/− mice (Lagranha et al, 2014). These results support the findings showing increased glutamate binding to Na + ‐dependent transporters (Busanello et al, 2014). Higher expression of the glutamate transporter subunits GLAST and GLT1 was also seen in cerebral cortex and striatum of adult Gcdh −/− mice, whereas in infant mice only GLAST mRNA levels were augmented in striatum.…”

Section: Glutamatergic and Gabaergic Neurotransmission Impairment In supporting

confidence: 92%

Pathogenesis of brain damage in glutaric acidemia type I: Lessons from the genetic mice model

Wajner

Amaral

Leipnitz

2019

Intl J of Devlp Neuroscience

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Glutaric acidemia type I (GA I) is an inherited neurometabolic disease caused by deficient activity of the mitochondrial enzyme glutaryl‐CoA dehydrogenase (GCDH), resulting in predominant accumulation of glutaric and 3‐hydroxyglutaric acids derived from lysine (Lys), hydroxylysine, and tryptophan catabolism. GA I patients usually present progressive cortical leukodystrophy and frequently develop acute striatal degeneration during encephalopathic crises during the first three years of life. The pathophysiology of the neurodegeneration observed in GA I is still partly known, although the development of the genetic mice model of GA I (Gcdh−/−) has contributed to clarify potential underlying mechanisms involved in brain damage in this disease. In this review we will summarize the knowledge acquired from studies using this animal model indicating that disruption of redox homeostasis, glutamatergic neurotransmission and bioenergetics, as well as vascular alterations, blood‐brain barrier breakage and altered myelination underlie the cortical and striatum abnormalities and white matter changes observed in GA I patients. Elucidation of these pathomechanisms potentially offers new standpoints for the development of novel therapeutic strategies for this disease.

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Section: Glutamatergic and Gabaergic Neurotransmission Impairment In supporting

confidence: 92%

Pathogenesis of brain damage in glutaric acidemia type I: Lessons from the genetic mice model

Wajner

Amaral

Leipnitz

2019

Intl J of Devlp Neuroscience

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“…Furthermore, analysis of amplitude, rise time, and decay time constant of these inhibitory responses on neocortical pyramidal cells of Gcdh −/− ‐ Lys animals showed no changes when compared to controls. Similar changes could be expected in the striatum GA‐I once alterations of the glutamatergic system and increased concentrations of the accumulating organic acids have been reported in this structure in GA‐I . In this context, our work focused on neocortex, and further investigation on striatum shall be carried out in the future.…”

Section: Discussionsupporting

confidence: 72%

“…Similar changes could be expected in the striatum GA-I once alterations of the glutamatergic system and increased concentrations of the accumulating organic acids have been reported in this structure in GA-I. 12,29,40 In this context, our work focused on neocortex, and further investigation on striatum shall be carried out in the future.…”

Section: Discussionsupporting

confidence: 70%

“…Up to now, the investigation of increased excitability has been focused mainly on glutamatergic neurotransmission . Three important findings have been reported relating glutamatergic system to alterations in GA‐I: (1) GA inhibits the glutamate uptake; (2) neuronal death induced by the organic acids in GA‐I can be prevented by in vitro preincubation of N ‐methyl‐ d ‐aspartate (NMDA) antagonists; and (3) pretreatment with MK‐801, a noncompetitive NMDA antagonist, prevents seizures induced by intra‐striatal injection of glutaric acids . However, dysfunction in the GABAergic system could also play a crucial role in GA‐I neuropathology, and here we were able to demonstrate important implications of this system in GA‐I.…”

Section: Discussionmentioning

confidence: 99%

“…10 Various reports show that AG and 3-OHAG induce an imbalance between glutamate and GABA release and oxidative damage in the central nervous system (CNS) leading to hyperexcitability. 2,8,9,[11][12][13][14] GABAergic interneurons play a central role, not only in modulation and synchronization of pyramidal cells activity, 15 but also in neurodevelopment, migration, proliferation, and synaptic formation, crucial for the neuronal network. [16][17][18] Deficits in GABAergic system are associated with central CNS disorders such as epilepsy.…”

mentioning

confidence: 99%

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Impairment of GABAergic system contributes to epileptogenesis in glutaric acidemia type I

et al. 2017

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Using an experimental model with a phenotype similar to that of GA-I in humans-the Gcdh mice under high lysine diet (Gcdh -Lys)-we provide evidence that a reduction in cortical inhibition of Gcdh -Lys mice, probably induced by GAD dysfunction, leads to hyperexcitability and increased slow oscillations associated with neurologic abnormalities in GA-I. Our findings offer a new perspective on the pathophysiology of brain damage in GA-I.

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Higher Vulnerability of Menadione-Exposed Cortical Astrocytes of Glutaryl-CoA Dehydrogenase Deficient Mice to Oxidative Stress, Mitochondrial Dysfunction, and Cell Death: Implications for the Neurodegeneration in Glutaric Aciduria Type I

et al. 2016

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Patients affected by glutaric aciduria type I (GA-I) show progressive cortical leukoencephalopathy whose pathogenesis is poorly known. In the present work, we exposed cortical astrocytes of wild-type (Gcdh ) and glutaryl-CoA dehydrogenase knockout (Gcdh ) mice to the oxidative stress inducer menadione and measured mitochondrial bioenergetics, redox homeostasis, and cell viability. Mitochondrial function (MTT and JC1-mitochondrial membrane potential assays), redox homeostasis (DCFH oxidation, nitrate and nitrite production, GSH concentrations and activities of the antioxidant enzymes SOD and GPx), and cell death (propidium iodide incorporation) were evaluated in primary cortical astrocyte cultures of Gcdh and Gcdh mice unstimulated and stimulated by menadione. We also measured the pro-inflammatory response (TNFα levels, IL1-β and NF-ƙB) in unstimulated astrocytes obtained from these mice. Gcdh mice astrocytes were more vulnerable to menadione-induced oxidative stress (decreased GSH concentrations and altered activities of the antioxidant enzymes), mitochondrial dysfunction (decrease of MTT reduction and JC1 values), and cell death as compared with Gcdh astrocytes. A higher inflammatory response (TNFα, IL1-β and NF-ƙB) was also observed in Gcdh mice astrocytes. These data indicate a higher susceptibility of Gcdh cortical astrocytes to oxidative stress and mitochondrial dysfunction, probably leading to cell death. It is presumed that these pathomechanisms may contribute to the cortical leukodystrophy observed in GA-I patients.

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Disturbance of the glutamatergic system by glutaric acid in striatum and cerebral cortex of glutaryl-CoA dehydrogenase-deficient knockout mice: Possible implications for the neuropathology of glutaric acidemia type I

Cited by 13 publications

References 54 publications

Pathogenesis of brain damage in glutaric acidemia type I: Lessons from the genetic mice model

Pathogenesis of brain damage in glutaric acidemia type I: Lessons from the genetic mice model

Impairment of GABAergic system contributes to epileptogenesis in glutaric acidemia type I

Higher Vulnerability of Menadione-Exposed Cortical Astrocytes of Glutaryl-CoA Dehydrogenase Deficient Mice to Oxidative Stress, Mitochondrial Dysfunction, and Cell Death: Implications for the Neurodegeneration in Glutaric Aciduria Type I

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