Impairment of <scp>GABA</scp>ergic system contributes to epileptogenesis in glutaric acidemia type I

Pasquetti, Mayara Vendramin; Pereira, Leticia; Loureiro, Samanta Oliveira; Ganzella, Marcelo; Junges, Bernardo; Caus, Letícia Barbieri; Amaral, Alexandre Umpierrez; Koeller, David M.; Goodman, Stephen I.; Woontner, Michael; Souza, Diogo O.; Wajner, Moaçir; Calcagnotto, María Elisa

doi:10.1111/epi.13862

Cited by 16 publications

(16 citation statements)

References 41 publications

(96 reference statements)

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“…Lower GABA levels were attributed to inhibition of glutamate decarboxylase activity by GA and 3−OHGA (Stokke et al, 1976). Severe changes of electrophysiological findings observed in the Gcdh −/− mice also suggest disruption of GABAergic neurotransmission system in GA I (Vendramin Pasquetti et al, 2017).…”

Section: Glutamatergic and Gabaergic Neurotransmission Impairment In mentioning

confidence: 98%

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 mentioning

confidence: 98%

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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“…At least 100 individual events were manually selected for each cell to analyze the synaptic currents (EPSCs or IPSCs) (Cobos et al, 2005;Cubelos et al, 2010;Vendramin Pasquetti et al, 2017). The EPSC and IPSC frequency, amplitude, 10-90% rise time and decay time constant were measured using Mini Analysis 6.0.7 (Synaptosoft Software).…”

Section: Discussionmentioning

confidence: 99%

“…Acute brain slices were prepared for physiological recordings as described previously (Cobos et al, 2005;Vendramin Pasquetti et al, 2017). Males and females were anesthetized with ketamine and xylazine (80 mg/kg and 10 mg/kg intraperitoneally, respectively) and were quickly decapitated.…”

Section: Slice Preparationmentioning

confidence: 99%

“…Serial sections (300 µm) were cut using a vibrating microtome (VTS-1000; Leica, Germany) at 4°C oxygenated sACSF. The slices from the left and right hemispheres were separated and immediately transferred to a chamber to remain immersed in oxygenated normalrecording artificial cerebrospinal fluid (nACSF) consisting of 124 mM NaCl, 3 mM KCl, 1.25 mM NaH 2 PO 4 , 2 mM MgSO 4 , 26 mM NaHCO 3 , 1 mM CaCl 2 and 10 mM dextrose (295-305 mOsm, pH 7.4) (Cobos et al, 2005;Vendramin Pasquetti et al, 2017). The slices were bubbled with 95% O 2 /5% CO 2 and maintained at 37°C for 45 min and, afterwards, at RT.…”

Section: Slice Preparationmentioning

confidence: 99%

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Sexual dimorphism, estrous cycle and laterality determine the intrinsic and synaptic properties of medial amygdala neurons in rat

Dalpian

Rasia‐Filho

Calcagnotto

2019

Journal of Cell Science

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The posterodorsal medial amygdala (MePD) is a sex steroid-sensitive area that modulates different social behavior by relaying chemosensorial information to hypothalamic nuclei. However, little is known about MePD cell type diversity and functional connectivity. Here, we have characterized neurons and synaptic inputs in the right and left MePD of adult male and cycling female (in diestrus, proestrus or estrus) rats. Based on their electrophysiological properties and morphology, we found two coexisting subpopulations of spiny neurons that are sexually dimorphic. They were classified as Class I ( predominantly bitufted-shaped neurons showing irregular spikes with frequency adaptation) or Class II ( predominantly stellate-shaped neurons showing full spike frequency adaptation). Furthermore, excitatory and inhibitory inputs onto MePD cells were modulated by sex, estrous cycle and hemispheric lateralization. In the left MePD, there was an overall increase in the excitatory input to neurons of males compared to cycling females. However, in proestrus, the MePD neurons received mainly inhibitory inputs. Our findings indicate the existence of hemispheric lateralization, estrous cycle and sexual dimorphism influences at cellular and synaptic levels in the adult rat MePD.

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“…Impairment of GABA ergic function has the potential to lower seizure threshold or produce convulsions outright [14]. Although DOMBA reduced GABA-elicited current in vitro, it seemed possible DOMBA might also cause seizures in vivo.…”

Section: Discussionmentioning

confidence: 99%

In vitro and in vivo GABA<sub>A</sub> Receptor Interaction of the Propanidid Metabolite 4-(2-[Diethylamino]-2-Oxoethoxy)-3-Methoxy-Benzeneacetic Acid

2018

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Background: Propanidid is a γ-aminobutyric acid type A (GABA_A) receptor agonist general anesthetic and its primary metabolite is 4-(2-[diethylamino]-2-oxoethoxy)-3-methoxy-benzeneacetic acid (DOMBA). Despite having a high water solubility at physiologic pH that might predict low-affinity GABA_A receptor interactions, DOMBA is reported to have no effect on GABA_A receptor currents, possibly because the DOMBA concentrations studied were simply insufficient to modulate GABA_A receptors. Our objectives were to measure the propanidid and DOMBA concentration responses on GABA_A receptors and to measure the behavioral responses of DOMBA in mice at concentrations that affect GABA_A receptor currents in vitro. Methods: GABA_A receptors were expressed in oocytes using clones for the human GABA_A α₁, β₂ and γ_2s subunits. The effects of DOMBA (0.2–10 mmol/L) and propanidid (0.001–1 mmol/L) on oocyte GABA_A currents were studied using standard 2-electrode voltage clamp techniques. Based on in vitro results, 6 mice received DOMBA 32 mg intraperitoneal and were observed for occurrence of neurologic effects and DOMBA plasma concentration was measured by liquid chromatography tandem mass spectrometry. Results: DOMBA both directly activates GABA_A receptors and antagonizes its GABA-mediated opening in a concentration-dependent manner at concentrations between 5–10 and 0.5–10 mmol/L respectively. In vivo, DOMBA produced rapid onset sedation at plasma concentrations that correlate with direct GABA_A receptor activation. Conclusion: DOMBA modulation of GABA_A receptors is associated with sedation in mice. Metabolites of propanidid analogues currently in development may similarly modulate GABA_A, and impaired elimination of these metabolites could produce clinically relevant neurophysiologic effects.

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

Cited by 16 publications

References 41 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

Sexual dimorphism, estrous cycle and laterality determine the intrinsic and synaptic properties of medial amygdala neurons in rat

In vitro and in vivo GABA<sub>A</sub> Receptor Interaction of the Propanidid Metabolite 4-(2-[Diethylamino]-2-Oxoethoxy)-3-Methoxy-Benzeneacetic Acid

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