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

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  • K R Drasbek
  • I Vardya, Denmark
  • M Delenclos, Denmark
  • K M Gibson, Denmark
  • Kimmo Jensen, Denmark
  • Department of Physiology and Biophysics
  • Department of Molecular Biology
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.
Original languageEnglish
JournalJournal of Inherited Metabolic Disease
Pages (from-to)662-8
Number of pages6
Publication statusPublished - 2008

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