PROJECT SUMMARY We and others have shown that stimulation or potentiation of metabotropic glutamate receptor 5 (mGlu5) reverses cognitive deficits in rodent models relevant for schizophrenia and other neurological disorders. We have also made the discovery that co-activation of another mGlu receptor subtype, termed mGlu3, dramatically potentiates mGlu5 signaling in the hippocampus as well as in in vitro culture systems. We demonstrate here that co-activation of mGlu3 and mGlu5 induces hippocampal long-term potentiation (LTP) and potentiates induction of LTP by afferent stimulation. Furthermore, mGlu3 activation enhances hippocampal-dependent learning in an mGlu5-dependent manner. Using mice in which mGlu3 or mGlu5 can be deleted in a cell-type specific pattern, we have also found that loss of either receptor from hippocampal pyramidal cells eliminates the ability of mGlu3 agonists to enhance long-term potentiation or improve performance in a hippocampal-dependent cognitive task. These findings provide a mechanistic bridge to genome-wide association studies (GWAS) and other human genetic studies showing associations between polymorphisms in the GRM3 gene and impaired cognitive function in schizophrenia patients. Additional co-expression studies suggest that this specific mGlu3/mGlu5 cross-talk may also occur in other brain regions that are critical for cognitive deficits in schizophrenia, such as the prefrontal cortex (PFC). For example, mGlu5 also regulates PFC-dependent cognitive function and our preliminary data suggest that activation of mGlu5 induces a novel form of LTP at excitatory synapses from the amygdala projections onto a specific population of inhibitory interneurons that express somatostatin (SST-INs). Mechanistically, these may reverse reductions in PFC inhibitory transmission that are associated with cognitive and negative symptoms of schizophrenia. Both mGlu3 and mGlu5 are expressed in SST-INs, and both have been implicated in forms of memory that depend on activation of SST-INs. We have also found evidence for specific signaling interactions between mGlu3 and mGlu5 in SST-INs. Based on these results, we postulate that mGlu3 and mGlu5 interact to induce LTP in PFC SST-INs. Furthermore, we hypothesize that either mGlu5 PAMs or mGlu3 agonists will enhance forms of cognition that require activation of SST-INs in the PFC, and that this response will be increased upon co-activation of these receptors. Using mGlu3 and mGlu5 subtype-selective modulators, mice lacking each receptor in a cell-type specific pattern, as well as chemogenetic, optogenetic, and a Drugs Acutely Restricted by Tethering (DART) approach to modulate activity of specific neuronal populations, we will test the hypothesis that mGlu3 activation enhances multiple other forms of cognitive function that are regulated by mGlu5 potentiation. Finally, we will determine if this mGlu3/5 interaction is intact after juvenile exposure of rodents to phencyclidine, which induces c...