# Regulation of Signaling by mGluR5

> **NIH NIH R01** · VANDERBILT UNIVERSITY · 2022 · $601,065

## Abstract

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...

## Key facts

- **NIH application ID:** 10439963
- **Project number:** 2R01MH062646-22A1
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** P Jeffrey Conn
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $601,065
- **Award type:** 2
- **Project period:** 2001-02-15 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10439963

## Citation

> US National Institutes of Health, RePORTER application 10439963, Regulation of Signaling by mGluR5 (2R01MH062646-22A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10439963. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*