GABA transporter-1 deficiency confers schizophrenia-like behavioral phenotypes.
The mechanism underlying the pathogenesis of schizophrenia remains poorly understood. The hyper-dopamine and hypo-NMDA receptor hypotheses have been the most enduring ideas. Recently, emerging evidence implicates alterations of the major inhibitory system, GABAergic neurotransmission in the schizophrenic patients. However, the pathophysiological role of GABAergic system in schizophrenia still remains dubious. In this study, we took advantage of GABA transporter 1 (GAT1) knockout (KO) mouse, a unique animal model with elevated ambient GABA, to study the schizophrenia-related behavioral abnormalities. We found that GAT1 KO mice displayed multiple behavioral abnormalities related to schizophrenic positive, negative and cognitive symptoms. Moreover, GAT1 deficiency did not change the striatal dopamine levels, but significantly enhanced the tonic GABA currents in prefrontal cortex. The GABA(A) receptor antagonist picrotoxin could effectively ameliorate several behavioral defects of GAT1 KO mice. These results identified a novel function of GAT1, and indicated that the elevated ambient GABA contributed critically to the pathogenesis of schizophrenia. Furthermore, several commonly used antipsychotic drugs were effective in treating the locomotor hyperactivity in GAT1 KO mice, suggesting the utility of GAT1 KO mice as an alternative animal model for studying schizophrenia pathogenesis and developing new antipsychotic drugs.
Institute of Neuroscience and State Key Laboratory of Neuroscience, Chinese Academy of Sciences, Shanghai, China.
Zhe
Z
Yu
Qi
Q
Fang
Xian
X
Xiao
Yi-Zhi
YZ
Wang
You-Qing
YQ
Cai
Hui
H
Cao
Gang
G
Hu
Zhong
Z
Chen
Jian
J
Fei
Neng
N
Gong
Tian-Le
TL
Xu
D000818:Animals; D015153:Blotting, Western; D004594:Electrophysiology; D050485:GABA Plasma Membrane Transport Proteins / Q000172:deficiency* / Q000235:genetics; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism*
D050485:GABA Plasma Membrane Transport Proteins