SSADH deficiency leads to elevated extracellular GABA levels and increased GABAergic neurotransmission in the mouse cerebral cortex

Succinic semialdehyde dehydrogenase (SSADH) deficiency is an inherited disorder in which patients display neurodevelopmental retardation, ataxia, and epileptic seizures. The recently engineered SSADH knock-out (KO) mouse models the severe form of the human disorder. The SSADH enzyme participates in...

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Bibliographic Details
Published in:Journal of inherited metabolic disease 2008-12, Vol.31 (6), p.662-668
Main Authors: Drasbek, K. R, Vardya, I, Delenclos, M, Gibson, K. M, Jensen, K
Format: Article
Language:English
Subjects:
Animals
Biochemistry
Biological and medical sciences
Brain
Cerebral Cortex - metabolism
Electrophysiology - methods
Female
gamma-Aminobutyric Acid - metabolism
Gene Expression Regulation
Heterozygote
Human Genetics
Humans
Internal Medicine
Male
Medical genetics
Medical sciences
Medicine
Medicine & Public Health
Metabolic Diseases
Mice
Mice, Knockout
Models, Biological
Pediatrics
Rapid Communication
Receptors, GABA-A - metabolism
Succinate-Semialdehyde Dehydrogenase - deficiency
Succinate-Semialdehyde Dehydrogenase - metabolism
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Summary:Succinic semialdehyde dehydrogenase (SSADH) deficiency is an inherited disorder in which patients display neurodevelopmental retardation, ataxia, and epileptic seizures. The recently engineered SSADH knock-out (KO) mouse models the severe form of the human disorder. The SSADH enzyme participates in the breakdown of the inhibitory neurotransmitter GABA, and studies have shown increases in brain GABA and downregulation of GABAA receptor β₂ subunits in the cerebral cortex of these mice. Here, we used brain slice electrophysiology to investigate the alterations in GABA neurotransmission in SSADH KO mouse cortex. In layer 2/3 pyramidal cells, spontaneous inhibitory postsynaptic currents (IPSCs), reflecting activity of GABAergic synaptic contacts, were normal in SSADH KO mice. Also, IPSCs evoked by electrical single-axon stimulation in KO mice were normal. In contrast, tonic inhibition mediated by presumed extrasynaptic GABAA receptors was strongly increased, indicating significantly raised extracellular GABA levels. The excessive cortical GABAergic neurotransmission may participate in the seizure activity in SSADH deficiency.
ISSN:0141-8955
1573-2665
DOI:10.1007/s10545-008-0941-7