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

Mayara Vendramin Pasquetti, Letícia Meier, Samanta Loureiro, Marcelo Ganzella, Bernardo Junges, Letícia Barbieri Caus, Alexandre Umpierrez Amaral, David Koeller, Stephen Goodman, Michael Woontner, Diogo Onofre Gomes de Souza, Moacir Wajner, Maria Elisa Calcagnotto

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Objectives: Glutaric acidemia type I (GA-I) is an inherited neurometabolic disorder caused by deficiency of glutaryl-CoA dehydrogenase (GCDH) and characterized by increased levels of glutaric, 3-OH-glutaric, and glutaconic acids in the brain parenchyma. The increment of these organic acids inhibits glutamate decarboxylase (GAD) and consequently lowers the γ-aminobutyric acid (GABA) synthesis. Untreated patients exhibit severe neurologic deficits during development, including epilepsy, especially following an acute encephalopathy outbreak. In this work, we evaluated the role of the GABAergic system on epileptogenesis in GA-I using the Gcdh-/- mice exposed to a high lysine diet (Gcdh-/--Lys). Methods: Spontaneous recurrent seizures (SRS), seizure susceptibility, and changes in brain oscillations were evaluated by video-electroencephalography (EEG). Cortical GABAergic synaptic transmission was evaluated using electrophysiologic and neurochemical approaches. Results: SRS were observed in 72% of Gcdh-/--Lys mice, whereas no seizures were detected in age-matched controls (Gcdh+/+ or Gcdh-/- receiving normal diet). The severity and number of PTZ-induced seizures were higher in Gcdh-/--Lys mice. EEG spectral analysis showed a significant decrease in theta and gamma oscillations and predominant delta waves in Gcdh-/--Lys mice, associated with increased EEG left index. Analysis of cortical synaptosomes revealed a significantly increased percentage of glutamate release and decreased GABA release in Gcdh-/--Lys mice that were associated with a decrease in cortical GAD immunocontent and activity and confirmed by reduced frequency of inhibitory events in cortical pyramidal cells. Significance: 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.

Original languageEnglish (US)
JournalEpilepsia
DOIs
StateAccepted/In press - 2017

Fingerprint

Seizures
Glutamate Decarboxylase
Electroencephalography
Diet
gamma-Aminobutyric Acid
Lysine
Brain
Nervous System Malformations
Aminobutyrates
Synaptosomes
Pyramidal Cells
Brain Diseases
Neurologic Manifestations
Glutaric Acidemia I
Synaptic Transmission
Disease Outbreaks
Glutamic Acid
Epilepsy
Theoretical Models
Phenotype

Keywords

  • Epilepsy
  • GABA
  • GAD
  • Glutaryl-CoA dehydrogenase deficiency
  • Synaptic transmission

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Vendramin Pasquetti, M., Meier, L., Loureiro, S., Ganzella, M., Junges, B., Barbieri Caus, L., ... Calcagnotto, M. E. (Accepted/In press). Impairment of GABAergic system contributes to epileptogenesis in glutaric acidemia type I. Epilepsia. https://doi.org/10.1111/epi.13862

Impairment of GABAergic system contributes to epileptogenesis in glutaric acidemia type I. / Vendramin Pasquetti, Mayara; Meier, Letícia; Loureiro, Samanta; Ganzella, Marcelo; Junges, Bernardo; Barbieri Caus, Letícia; Umpierrez Amaral, Alexandre; Koeller, David; Goodman, Stephen; Woontner, Michael; Gomes de Souza, Diogo Onofre; Wajner, Moacir; Calcagnotto, Maria Elisa.

In: Epilepsia, 2017.

Research output: Contribution to journalArticle

Vendramin Pasquetti, M, Meier, L, Loureiro, S, Ganzella, M, Junges, B, Barbieri Caus, L, Umpierrez Amaral, A, Koeller, D, Goodman, S, Woontner, M, Gomes de Souza, DO, Wajner, M & Calcagnotto, ME 2017, 'Impairment of GABAergic system contributes to epileptogenesis in glutaric acidemia type I', Epilepsia. https://doi.org/10.1111/epi.13862
Vendramin Pasquetti M, Meier L, Loureiro S, Ganzella M, Junges B, Barbieri Caus L et al. Impairment of GABAergic system contributes to epileptogenesis in glutaric acidemia type I. Epilepsia. 2017. https://doi.org/10.1111/epi.13862
Vendramin Pasquetti, Mayara ; Meier, Letícia ; Loureiro, Samanta ; Ganzella, Marcelo ; Junges, Bernardo ; Barbieri Caus, Letícia ; Umpierrez Amaral, Alexandre ; Koeller, David ; Goodman, Stephen ; Woontner, Michael ; Gomes de Souza, Diogo Onofre ; Wajner, Moacir ; Calcagnotto, Maria Elisa. / Impairment of GABAergic system contributes to epileptogenesis in glutaric acidemia type I. In: Epilepsia. 2017.
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abstract = "Objectives: Glutaric acidemia type I (GA-I) is an inherited neurometabolic disorder caused by deficiency of glutaryl-CoA dehydrogenase (GCDH) and characterized by increased levels of glutaric, 3-OH-glutaric, and glutaconic acids in the brain parenchyma. The increment of these organic acids inhibits glutamate decarboxylase (GAD) and consequently lowers the γ-aminobutyric acid (GABA) synthesis. Untreated patients exhibit severe neurologic deficits during development, including epilepsy, especially following an acute encephalopathy outbreak. In this work, we evaluated the role of the GABAergic system on epileptogenesis in GA-I using the Gcdh-/- mice exposed to a high lysine diet (Gcdh-/--Lys). Methods: Spontaneous recurrent seizures (SRS), seizure susceptibility, and changes in brain oscillations were evaluated by video-electroencephalography (EEG). Cortical GABAergic synaptic transmission was evaluated using electrophysiologic and neurochemical approaches. Results: SRS were observed in 72{\%} of Gcdh-/--Lys mice, whereas no seizures were detected in age-matched controls (Gcdh+/+ or Gcdh-/- receiving normal diet). The severity and number of PTZ-induced seizures were higher in Gcdh-/--Lys mice. EEG spectral analysis showed a significant decrease in theta and gamma oscillations and predominant delta waves in Gcdh-/--Lys mice, associated with increased EEG left index. Analysis of cortical synaptosomes revealed a significantly increased percentage of glutamate release and decreased GABA release in Gcdh-/--Lys mice that were associated with a decrease in cortical GAD immunocontent and activity and confirmed by reduced frequency of inhibitory events in cortical pyramidal cells. Significance: 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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T1 - Impairment of GABAergic system contributes to epileptogenesis in glutaric acidemia type I

AU - Vendramin Pasquetti, Mayara

AU - Meier, Letícia

AU - Loureiro, Samanta

AU - Ganzella, Marcelo

AU - Junges, Bernardo

AU - Barbieri Caus, Letícia

AU - Umpierrez Amaral, Alexandre

AU - Koeller, David

AU - Goodman, Stephen

AU - Woontner, Michael

AU - Gomes de Souza, Diogo Onofre

AU - Wajner, Moacir

AU - Calcagnotto, Maria Elisa

PY - 2017

Y1 - 2017

N2 - Objectives: Glutaric acidemia type I (GA-I) is an inherited neurometabolic disorder caused by deficiency of glutaryl-CoA dehydrogenase (GCDH) and characterized by increased levels of glutaric, 3-OH-glutaric, and glutaconic acids in the brain parenchyma. The increment of these organic acids inhibits glutamate decarboxylase (GAD) and consequently lowers the γ-aminobutyric acid (GABA) synthesis. Untreated patients exhibit severe neurologic deficits during development, including epilepsy, especially following an acute encephalopathy outbreak. In this work, we evaluated the role of the GABAergic system on epileptogenesis in GA-I using the Gcdh-/- mice exposed to a high lysine diet (Gcdh-/--Lys). Methods: Spontaneous recurrent seizures (SRS), seizure susceptibility, and changes in brain oscillations were evaluated by video-electroencephalography (EEG). Cortical GABAergic synaptic transmission was evaluated using electrophysiologic and neurochemical approaches. Results: SRS were observed in 72% of Gcdh-/--Lys mice, whereas no seizures were detected in age-matched controls (Gcdh+/+ or Gcdh-/- receiving normal diet). The severity and number of PTZ-induced seizures were higher in Gcdh-/--Lys mice. EEG spectral analysis showed a significant decrease in theta and gamma oscillations and predominant delta waves in Gcdh-/--Lys mice, associated with increased EEG left index. Analysis of cortical synaptosomes revealed a significantly increased percentage of glutamate release and decreased GABA release in Gcdh-/--Lys mice that were associated with a decrease in cortical GAD immunocontent and activity and confirmed by reduced frequency of inhibitory events in cortical pyramidal cells. Significance: 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.

AB - Objectives: Glutaric acidemia type I (GA-I) is an inherited neurometabolic disorder caused by deficiency of glutaryl-CoA dehydrogenase (GCDH) and characterized by increased levels of glutaric, 3-OH-glutaric, and glutaconic acids in the brain parenchyma. The increment of these organic acids inhibits glutamate decarboxylase (GAD) and consequently lowers the γ-aminobutyric acid (GABA) synthesis. Untreated patients exhibit severe neurologic deficits during development, including epilepsy, especially following an acute encephalopathy outbreak. In this work, we evaluated the role of the GABAergic system on epileptogenesis in GA-I using the Gcdh-/- mice exposed to a high lysine diet (Gcdh-/--Lys). Methods: Spontaneous recurrent seizures (SRS), seizure susceptibility, and changes in brain oscillations were evaluated by video-electroencephalography (EEG). Cortical GABAergic synaptic transmission was evaluated using electrophysiologic and neurochemical approaches. Results: SRS were observed in 72% of Gcdh-/--Lys mice, whereas no seizures were detected in age-matched controls (Gcdh+/+ or Gcdh-/- receiving normal diet). The severity and number of PTZ-induced seizures were higher in Gcdh-/--Lys mice. EEG spectral analysis showed a significant decrease in theta and gamma oscillations and predominant delta waves in Gcdh-/--Lys mice, associated with increased EEG left index. Analysis of cortical synaptosomes revealed a significantly increased percentage of glutamate release and decreased GABA release in Gcdh-/--Lys mice that were associated with a decrease in cortical GAD immunocontent and activity and confirmed by reduced frequency of inhibitory events in cortical pyramidal cells. Significance: 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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