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Impairment of GABAergic system contributes to epileptogenesis in glutaric acidemia type I
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Titel: |
Impairment of GABAergic system contributes to epileptogenesis in glutaric acidemia type I |
In: | Epilepsia, 58, 2017, 10, S. 1771-1781 |
veröffentlicht: |
Wiley
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Umfang: | 1771-1781 |
ISSN: |
1528-1167 0013-9580 |
DOI: | 10.1111/epi.13862 |
Zusammenfassung: | <jats:title>Summary</jats:title><jats:sec><jats:title>Objectives</jats:title><jats:p>Glutaric acidemia type I (<jats:styled-content style="fixed-case">GA</jats:styled-content>‐I) is an inherited neurometabolic disorder caused by deficiency of glutaryl‐CoA dehydrogenase (<jats:styled-content style="fixed-case">GCDH</jats:styled-content>) and characterized by increased levels of glutaric, 3‐<jats:styled-content style="fixed-case">OH</jats:styled-content>‐glutaric, and glutaconic acids in the brain parenchyma. The increment of these organic acids inhibits glutamate decarboxylase (<jats:styled-content style="fixed-case">GAD</jats:styled-content>) 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 <jats:styled-content style="fixed-case">GABA</jats:styled-content>ergic system on epileptogenesis in <jats:styled-content style="fixed-case">GA</jats:styled-content>‐I using the <jats:italic>Gcdh</jats:italic><jats:sup>−/−</jats:sup> mice exposed to a high lysine diet (<jats:italic>Gcdh</jats:italic><jats:sup>−/−</jats:sup><jats:italic>‐</jats:italic>Lys).</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Spontaneous recurrent seizures (<jats:styled-content style="fixed-case">SRS</jats:styled-content>), seizure susceptibility, and changes in brain oscillations were evaluated by video–electroencephalography (EEG). Cortical <jats:styled-content style="fixed-case">GABA</jats:styled-content>ergic synaptic transmission was evaluated using electrophysiologic and neurochemical approaches.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p><jats:styled-content style="fixed-case">SRS</jats:styled-content> were observed in 72% of <jats:italic>Gcdh</jats:italic><jats:sup>−/−</jats:sup><jats:italic>‐</jats:italic>Lys mice, whereas no seizures were detected in age‐matched controls (<jats:italic>Gcdh</jats:italic><jats:sup>+/+</jats:sup> or <jats:italic>Gcdh</jats:italic><jats:sup>−/−</jats:sup> receiving normal diet). The severity and number of <jats:styled-content style="fixed-case">PTZ</jats:styled-content>‐induced seizures were higher in <jats:italic>Gcdh</jats:italic><jats:sup>−/−</jats:sup><jats:italic>‐</jats:italic>Lys mice. <jats:styled-content style="fixed-case">EEG</jats:styled-content> spectral analysis showed a significant decrease in theta and gamma oscillations and predominant delta waves in <jats:italic>Gcdh</jats:italic><jats:sup>−/−</jats:sup><jats:italic>‐</jats:italic>Lys mice, associated with increased <jats:styled-content style="fixed-case">EEG</jats:styled-content> left index. Analysis of cortical synaptosomes revealed a significantly increased percentage of glutamate release and decreased <jats:styled-content style="fixed-case">GABA</jats:styled-content> release in <jats:italic>Gcdh</jats:italic><jats:sup>−/−</jats:sup><jats:italic>‐</jats:italic>Lys mice that were associated with a decrease in cortical <jats:styled-content style="fixed-case">GAD</jats:styled-content> immunocontent and activity and confirmed by reduced frequency of inhibitory events in cortical pyramidal cells.</jats:p></jats:sec><jats:sec><jats:title>Significance</jats:title><jats:p>Using an experimental model with a phenotype similar to that of <jats:styled-content style="fixed-case">GA</jats:styled-content>‐I in humans—the <jats:italic>Gcdh</jats:italic><jats:sup>−/−</jats:sup> mice under high lysine diet (<jats:italic>Gcdh</jats:italic><jats:sup>−/−</jats:sup><jats:italic>‐</jats:italic>Lys)—we provide evidence that a reduction in cortical inhibition of <jats:italic>Gcdh</jats:italic><jats:sup>−/−</jats:sup>‐Lys mice, probably induced by <jats:styled-content style="fixed-case">GAD</jats:styled-content> dysfunction, leads to hyperexcitability and increased slow oscillations associated with neurologic abnormalities in <jats:styled-content style="fixed-case">GA</jats:styled-content>‐I. Our findings offer a new perspective on the pathophysiology of brain damage in <jats:styled-content style="fixed-case">GA</jats:styled-content>‐I.</jats:p></jats:sec> |
Format: | E-Article |
Quelle: | Wiley (CrossRef) |
Sprache: | Englisch |