title: SSADH deficiency leads to elevated extracellular GABA levels and increased GABAergic neurotransmission in the mouse cerebral cortex.
abstract: 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 GABA(A) receptor beta(2) 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 GABA(A) receptors was strongly increased, indicating significantly raised extracellular GABA levels. The excessive cortical GABAergic neurotransmission may participate in the seizure activity in SSADH deficiency.
authors.affiliation: Synaptic Physiology Laboratory, Institute of Physiology and Biophysics, University of Aarhus, Aarhus, Denmark.
authors.forename: K R
authors.initials: KR
authors.lastname: Drasbek
authors.forename: I
authors.initials: I
authors.lastname: Vardya
authors.forename: M
authors.initials: M
authors.lastname: Delenclos
authors.forename: K M
authors.initials: KM
authors.lastname: Gibson
authors.forename: K
authors.initials: K
authors.lastname: Jensen
mesh_terms: D000818:Animals; D001921:Brain; D002540:Cerebral Cortex / Q000378:metabolism*; D004594:Electrophysiology / Q000379:methods; D005260:Female; D005786:Gene Expression Regulation; D006579:Heterozygote; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D011963:Receptors, GABA-A / Q000378:metabolism*; D050644:Succinate-Semialdehyde Dehydrogenase / Q000172:deficiency* / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D050644:Succinate-Semialdehyde Dehydrogenase