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

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.