期刊
BIOLOGICAL PSYCHIATRY
卷 64, 期 9, 页码 810-814出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.biopsych.2008.05.001
关键词
GLAST; glutamate; mGlu2/3; NMDA; schizophrenia
资金
- National Institute on Alcohol Abuse and Alcoholism (AMAA)-Intramural Research Program (IRP)
- The Novartis Foundation (Japan)
- The Tokyo Biochemical Research Foundation
- Research Foundation of Opto-Science and Technology
- Ministry of Education, Culture, Sports, Science, and Technology of Japan [20022013, 18053006]
- Grants-in-Aid for Scientific Research [20022013, 18053006] Funding Source: KAKEN
Background: Recent data suggest that excessive glutamatergic signaling in the prefrontal cortex may contribute to the pathophysiology of schizophrenia and that promoting presynaptic glutamate modulation via group II metabotropic glutamate 2/3 (mGlu2/3) receptor activation can exert antipsychotic efficacy. The glial glutamate and aspartate transporter (GLAST) (excitatory amino acid transporter 1 [EAAT1]) regulates extracellular glutamate levels via uptake into glia, but the consequences of GLAST dysfunction for schizophrenia are largely unknown. Methods: We examined GLAST knockout mice (KO) for behaviors thought to model positive symptoms in schizophrenia (locomotor hyperactivity to novelty, exaggerated locomotor response to N-methyl-D-aspartate receptor [NMDAR] antagonism) and the ability of haloperidol and the mGlu2/3 agonist LY379268 to normalize novelty-induced hyperactivity. Results: Glial glutamate and aspartate transporter KO consistently showed locomotor hyperactivity to a novel but not familiar environment, relative to wild-type (WT) mice. The locomotor hyperactivity-inducing effects of the NMDAR antagonist MK-801 was exaggerated in GLAST KO relative to WT. Treatment with haloperidol or LY379268 normalized novelty-induced locomotor hyperactivity in GLAST KO. Conclusions: Schizophrenia-related abnormalities in GLAST KO raise the possibility that loss of GLAST-mediated glutamate clearance could be a pathophysiological risk factor for the disease. Our findings provide novel support for the hypothesis that glutamate dysregulation contributes to the pathophysiology of schizophrenia and for the antipsychotic potential of mGlu2/3 agonists.
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