title: Reduced tonic inhibition in striatal output neurons from Huntington mice due to loss of astrocytic GABA release through GAT-3.
abstract: The extracellular concentration of the two main neurotransmitters glutamate and GABA is low but not negligible which enables a number of tonic actions. The effects of ambient GABA vary in a region-, cell-type, and age-dependent manner and can serve as indicators of disease-related alterations. Here we explored the tonic inhibitory actions of GABA in Huntington's disease (HD). HD is a devastating neurodegenerative disorder caused by a mutation in the huntingtin gene. Whole cell patch clamp recordings from striatal output neurons (SONs) in slices from adult wild type mice and two mouse models of HD (Z_Q175_KI homozygotes or R6/2 heterozygotes) revealed an HD-related reduction of the GABA(A) receptor-mediated tonic chloride current (I(Tonic(GABA))) along with signs of reduced GABA(B) receptor-mediated presynaptic depression of synaptic GABA release. About half of I(Tonic(GABA)) depended on tetrodotoxin-sensitive synaptic GABA release, but the remaining current was still lower in HD. Both in WT and HD, I(Tonic(GABA)) was more prominent during the first 4 h after preparing the slices, when astrocytes but not neurons exhibited a transient depolarization. All further tests were performed within 1-4 h in vitro. Experiments with SNAP5114, a blocker of the astrocytic GABA transporter GAT-3, suggest that in WT but not HD GAT-3 operated in the releasing mode. Application of a transportable substrate for glutamate transporters (D-aspartate 0.1-1 mM) restored the non-synaptic GABA release in slices from HD mice. I(Tonic(GABA)) was also rescued by applying the hyperagonist gaboxadol (0.33 μM). The results lead to the hypothesis that lesion-induced astrocyte depolarization facilitates non-synaptic release of GABA through GAT-3. However, the capacity of depolarized astrocytes to provide GABA for tonic inhibition is strongly reduced in HD.
authors: Cluster of Excellence NeuroCure, University Medicine Charité Berlin, Germany ; Department of Experimental Neurology, University Medicine Charité Berlin, Germany.
authors: Anna M
authors: AM
authors: Wójtowicz
authors: Anton
authors: A
authors: Dvorzhak
authors: Marcus
authors: M
authors: Semtner
authors: Rosemarie
authors: R
authors: Grantyn
mesh_terms: D000818:Animals; D000840:Anisoles / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D018755:GABA Agonists / Q000494:pharmacology; D050485:GABA Plasma Membrane Transport Proteins / Q000378:metabolism*; D058805:GABA Uptake Inhibitors / Q000494:pharmacology; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D007555:Isoxazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009557:Nipecotic Acids / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: C092337:1-(2-(tris(4-methoxyphenyl)methoxy)ethyl)-3-piperidinecarboxylic acid; D000840:Anisoles; D018755:GABA Agonists; D050485:GABA Plasma Membrane Transport Proteins; D058805:GABA Uptake Inhibitors; D007555:Isoxazoles; D009557:Nipecotic Acids; D005680:gamma-Aminobutyric Acid; C015542:gaboxadol
keywords: GABA(A) receptor; GABA(B) receptor; GABAergic synaptic transmission; GAT-3; Huntington's disease; ambient GABA; astrocyte; presynaptic depression