GABAA-receptor modification in taurine transporter knockout mice causes striatal disinhibition.
The Striatum is involved in the regulation of movements and motor skills. We have shown previously, that the osmolyte and neuromodulator taurine plays a role in striatal plasticity. We demonstrate now that hereditary taurine deficiency in taurine-transporter knock-out (TAUT KO) mice results in disinhibition of striatal network activity, which can be corrected by taurine supplementation. Modification of GABAA but not glycine receptors (taurine is a ligand for both receptor types) underlies this disinhibition. Whole-cell recordings from acutely isolated as well as cultured striatal neurons revealed a decreased agonist sensitivity of the GABAA receptor in TAUT KO neurons in the absence of changes in the maximal GABA-evoked current amplitude. The striatal GABA level in TAUT KO mice was unchanged. The amplitude enhancement of spontaneous IPSCs by zolpidem was stronger in TAUT KO than in wild-type (WT) animals. Tonic inhibition was absent in striatal neurons under control conditions but was detected after incubation with the GABA-transaminase inhibitor vigabatrin: bicuculline induced a larger shift of baseline current in WT as compared to TAUT KO neurons. Lack of taurine leads to reduced sensitivity of synaptic and extrasynaptic GABAA receptors and consequently to disinhibition. These findings help in understanding neuropathologies accompanied by the loss of endogenous taurine, for instance in hepatic encephalopathy.
Sergeeva
O A
OA
Department of Neurophysiology, Heinrich-Heine-Universität, Physiology II, POB 101007, D-40001 Düsseldorf, Germany. olga.sergeeva@uni-duesseldorf.de
Fleischer
W
W
Chepkova
A N
AN
Warskulat
U
U
Häussinger
D
D
Siebler
M
M
Haas
H L
HL
D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000166:cytology / Q000502:physiology*; D005260:Female; D018682:GABA Agents / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009433:Neural Inhibition / Q000502:physiology*; D011963:Receptors, GABA-A / Q000502:physiology*; D013654:Taurine / Q000494:pharmacology; D020888:Vigabatrin / Q000494:pharmacology; D000099247:Taurine Transporters
D001640:Bicuculline; D018682:GABA Agents; D018756:GABA Antagonists; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D011963:Receptors, GABA-A; D013654:Taurine; D020888:Vigabatrin; D000099247:Taurine Transporters