Functions of Metabotropic Glutamate Receptor Subtypes

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Emerging, preclinical, clinical, and human genetic studies raise the exciting possibility that selective activators of the mGlu1 subtype of metabotropic glutamate (mGlu) receptor have potential utility as a novel approach for treatment for schizophrenia. However, until recently, tools were not available to allow studies of the functional roles of mGlu1 in specific brain circuits. We have now developed highly selective mGlu1 positive allosteric modulators (PAMs), along with genetic mouse lines that allow selective deletion of mGlu1 in specific neuronal populations. This provides an unprecedented opportunity to establish the roles of mGlu1 in specific brain circuits that are disrupted in schizophrenia patients. Interestingly, we recently found that highly selective mGlu1 PAMs reduce striatal dopamine (DA) release and have robust efficacy in rodent models of antipsychotic activity, such as reversal of amphetamine-induced hyper-locomotor activity and disruption of sensory motor gating. Based on recent studies and our preliminary data, we postulate that activation of mGlu1 in a specific population of spinal projection neurons that also express the D1-DA receptor (D1-SPNs) is responsible for the ability of mGlu1 PAMs to inhibit DA release and to reverse behavioral effects of amphetamine that are relevant for potential antipsychotic activity. However, it is possible that activation of mGlu1 in DA terminals or other neuronal populations could be responsible for these effects on DA release and for the behavioral effects of mGlu1 PAMs. Thus, we will perform a series of studies in specific aim 1 to rigorously evaluate the importance of mGlu1 in D1-SPNs and other neuronal populations in the effects of mGlu1 PAMs on DA release and associated behaviors. In addition to dysregulation of striatal DA release, multiple clinical and preclinical studies suggest that loss of GABAergic inhibitory transmission in the prefrontal cortex (PFC) and other forebrain regions may play a critical role in the pathophysiological changes underlying cognitive deficits in schizophrenia patients. Additionally, disinhibition is observed in humans and rodents in response to NMDA receptor blockade. We now present exciting new preliminary data suggesting that activation of mGlu1 can increase activity of somatostatin-expressing inhibitory interneurons (SST-INs) and parvalbumin (PV)-expressing interneurons (PV- INs) in the PFC, with an especially robust increase in excitability of SST-INs. In addition, our preliminary data suggest that SST-INs in the PFC are critical for working memory, and led us to postulate that activation of mGlu1 on SST-INs may improve working memory and reverse working memory deficits in rodent models. In specific aim 2 we confirm our preliminary electrophysiology findings and rigorously test the hypothesis that mGlu1 activation increases inhibitory transmission in the PFC by actions on SSN-INs. In specific aim 3, we will test the hypothesis that activation of mGlu1 in SST-INs can reverse deficits in working memory and other behavioral deficits observed in an NMDAR hypofunction model of cortical disinhibition. These studies could provide new mechanistic insights into the therapeutic potential of mGlu1 PAMs for treatment of schizophrenia.