Metabotropic glutamate receptor 3 activation is required for long-term depression in medial prefrontal cortex and fear extinction

Adam G. Walker, Cody J. Wenthur, Zixiu Xiang, Jerri M. Rook, Kyle A. Emmitte, Colleen M. Niswender, Craig W. Lindsley, P. Jeffrey Conn

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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.

Original languageEnglish
Pages (from-to)1196-1201
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number4
StatePublished - 27 Jan 2015



  • Fear extinction
  • GRM3
  • Group II mGlu receptors
  • Long-term depression
  • Medial prefrontal cortex

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