Input-specific regulation of glutamatergic synaptic transmission in the medial prefrontal cortex by mGlu2/mGlu4 receptor heterodimers

Synapse-specific partnershipNeurotransmission between the thalamus and medial prefrontal cortex (mPFC) in the brain regulates working memory and goal-directed and social dominance behaviors. Increased activity at synapses between the thalamus and the mPFC is implicated in some symptoms of schizophrenia and is attributed in part to reduced activity of the metabotropic glutamate receptor mGluR2. Using selective pharmacological agents on mouse brain slices, Xiang et al. found that mGluR2 formed functional heterodimers with mGluR4 selectively at inputs from the thalamus to the mPFC, but not those from the hippocampus or amygdala, which regulate other critical cognitive functions. The findings could lead to highly targeted treatments for a set of behaviors associated with schizophrenia and related disorders.Metabotropic glutamate receptors (mGluRs) are G protein–coupled receptors that regulate various aspects of central nervous system processing in normal physiology and in disease. They are thought to function as disulfide-linked homodimers, but studies have suggested that mGluRs can form functional heterodimers in cell lines. Using selective allosteric ligands, ex vivo brain slice electrophysiology, and optogenetic approaches, we found that two mGluR subtypes—mGluR2 and mGluR4 (or mGlu2 and mGlu4)—exist as functional heterodimers that regulate excitatory transmission in a synapse-specific manner within the rodent medial prefrontal cortex (mPFC). Activation of mGlu2/mGlu4 heterodimers inhibited glutamatergic signaling at thalamo-mPFC synapses but not at hippocampus-mPFC or amygdala-mPFC synapses. These findings raise the possibility that selectively targeting these heterodimers could be a therapeutic strategy for some neurologic and neuropsychiatric disorders involving specific brain circuits.