Modulation of pyramidal cell output in the medial prefrontal cortex by mGluR5 interacting with CB1

► mGluR5 activation increases output of pyramidal cells in the medial prefrontal cortex (mPFC). ► mGluR5 positive allosteric modulator (PAM) increases excitatory drive onto pyramidal cells. ► The direct facilitatory effect of the mGluR5 PAM involves a postsynaptic action on pyramidal cells. ► mGluR5 PAM also decreases synaptic inhibition through activation of presynaptic CB1 receptors. ► mGluR5 are useful targets to fine-tune mPFC output function.