# Functions of Metabotropic Glutamate Receptor Subtypes

> **NIH NIH R01** · VANDERBILT UNIVERSITY · 2021 · $484,535

## Abstract

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 i...

## Key facts

- **NIH application ID:** 10205709
- **Project number:** 2R01NS031373-27
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** P Jeffrey Conn
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $484,535
- **Award type:** 2
- **Project period:** 1993-08-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10205709

## Citation

> US National Institutes of Health, RePORTER application 10205709, Functions of Metabotropic Glutamate Receptor Subtypes (2R01NS031373-27). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10205709. Licensed CC0.

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