Homeostatic plasticity of GABAergic synaptic transmission in mice lacking GAT1.
GABA transporter-1 (GAT1) plays a key role in GABA reuptake, and deletion of GAT1 leads to a largely increased GABA-induced tonic conductance in the GAT1(-/-) mice. We hypothesized that homeostatic plasticity of GABA(A) receptor-mediated inhibition takes place to balance the increased tonic inhibition and maintains stability of the nervous system. In this study, we employed the loss of righting reflex assay and compared the behavioral difference of three animal models, mice with acute, partial, and permanent GAT1 deficiency, to confirm our hypothesis. Our data demonstrated that both acute and partial block of GAT1 increased the sensitivity of mice to GABAergic sedative/hypnotic drugs, whereas permanent GAT1 dysfunction in the GAT1(-/-) mice decreased the sensitivity to some extent. These results confirmed our presumption about the down-regulation of phasic GABAergic transmission in the GAT1 knockout mice. Moreover, electrophysiological measurements performed on slices from motor cortex suggested that it was the reduced GABA release, but not change of postsynaptic GABA receptors, which led to the down-regulation of phasic inhibition in GAT1(-/-) mice.
Xu
Yinfang
Y
Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, SIBS, CAS, Shanghai, China.
Cai
Youqing
Y
Gong
Neng
N
Chen
Chen
C
Wu
Yuncheng
Y
Zhang-Nunes
Sandy
S
Wang
Zhugang
Z
Xu
Tianle
T
Fei
Jian
J
D000818:Animals; D018755:GABA Agonists / Q000494:pharmacology; D050485:GABA Plasma Membrane Transport Proteins / Q000172:deficiency*; D006706:Homeostasis / Q000187:drug effects; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D051379:Mice; D009473:Neuronal Plasticity / Q000502:physiology*; D009557:Nipecotic Acids / Q000494:pharmacology; D010424:Pentobarbital / Q000494:pharmacology; D011930:Reaction Time / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D000078308:Tiagabine; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D018755:GABA Agonists; D050485:GABA Plasma Membrane Transport Proteins; D006993:Hypnotics and Sedatives; D009557:Nipecotic Acids; D005680:gamma-Aminobutyric Acid; D010424:Pentobarbital; D000078308:Tiagabine