期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：4
页码：1196-1201
DOI：10.1073/pnas.1416196112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceRecent genetic studies suggest that variations in the gene encoding metabotropic glutamate receptor 3 (mGlu3) can influence aspects of cognitive function that involve the prefrontal cortex (PFC). Furthermore, mutations in this gene may predispose individuals to developing psychiatric disorders in which altered function of the PFC has been implicated. However, little is known about the precise roles of mGlu3 in regulating the function of the PFC. In the present study, we took advantage of newly identified molecular probes to show that mGlu3 can strongly influence synaptic plasticity within the PFC and that blockade of this receptor impairs specific learning abilities in mice. These results suggest that mGlu3 may be a therapeutic target for cognitive dysfunction in mental disorders. Clinical studies have revealed that genetic variations in metabotropic glutamate receptor 3 (mGlu3) affect performance on cognitive tasks dependent upon the prefrontal cortex (PFC) and may be linked to psychiatric conditions such as schizophrenia, bipolar disorder, and addiction. We have performed a series of studies aimed at understanding how mGlu3 influences PFC function and cognitive behaviors. In the present study, we found that activation of mGlu3 can induce long-term depression in the mouse medial PFC (mPFC) in vitro. Furthermore, in vivo administration of a selective mGlu3 negative allosteric modulator impaired learning in the mPFC-dependent fear extinction task. The results of these studies implicate mGlu3 as a major regulator of PFC function and cognition. Additionally, potentiators of mGlu3 may be useful in alleviating prefrontal impairments associated with several CNS disorders.
关键词：GRM3 ; medial prefrontal cortex ; fear extinction ; long-term depression ; group II mGlu receptors
