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

• Published in: Journal of inherited metabolic disease Vol. 31; no. 6; pp. 662 - 668
• Main Authors: Drasbek, K. R, Vardya, I, Delenclos, M, Gibson, K. M, Jensen, K
• Format: Journal Article
• Language: English
• Published: Dordrecht Dordrecht : Springer Netherlands 01.12.2008; Springer Netherlands; Springer; Blackwell Publishing Ltd
• 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; Pyramidal Cell; Tonic Inhibition; Semialdehyde Dehydrogenase; Kynurenic Acid; SR95531; Cerebral cortex; Nutrition; Deficiency; Rodentia; Central nervous system; Metabolic diseases; Extracellular; Encephalon; Genetic disease; Vertebrata; Mammalia; Mouse; Animal; Neurotransmitter; GABA; Genetics; Blood lead level; Neurotransmission
• ISSN: 0141-8955; 1573-2665
• DOI: 10.1007/s10545-008-0941-7

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.