# Optopharmacological studies of presynaptic metabotropic glutamate receptor 2 in corticolimbic circuits

> **NIH NIH F31** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $18,540

## Abstract

ABSTRACT
Psychiatric disorders are extremely common throughout the human population and remain
among the most expensive and difficult illnesses to treat. Psychiatric disorders consist of many
types of conditions, including forms of anxiety and depression, which have many overlapping
symptoms, including cognitive deficits. In order to identify new drug targets to treat these
disorders, research has shifted beyond serotonergic and dopaminergic drugs, and has recently
focused on targeting the glutamatergic system in the brain. Glutamate is the most abundant
neurotransmitter in the brain, and plays a critical role in maintaining neurological homeostasis. A
major cause of psychiatric disorders is stress, which can affect glutamatergic signaling in
numerous ways. For these reasons, glutamate receptors are being evaluated as mediators of
disease pathophysiology and as potential treatment targets. Specifically, metabotropic
glutamate receptors (mGluRs) are G protein-coupled recepetors (GPCRs) which play a
neuromodulatory role in sensing and regulating glutamate release at the synapse. Preclinical and
clinical trials targeting mGluR2 and mGluR3, inhibitory Gi/o-coupled mGluRs, have shown some
promise in reducing anxiety. However, other trials have failed or had mixed results, indicating that
a more precise dissection of the role of mGluRs in the neurophysiology of psychiatric
disorders is needed. mGluR2 is a unique target at glutamate synapses due to its predominant
expression as a presynaptic autoreceptor, where it inhibits glutamate release and, following
prolonged activation, can causes long-term changes in synaptic strength. Importantly, mGluR2 is
highly expressed in the medial prefrontal cortex (mPFC) and the basolatoral amygdala (BLA),
key regions that regulate both mood and cognition. Disruption in the mPFC-BLA corticolimbic
circuit plays a key role in psychiatric disorders, and many human studies indicate connectivity
between these brain regions is disrupted in psychiatric patients. Some studies indicate that
mGluR2 plays a critical role in regulating neuronal activity in the mPFC and BLA, but the
underlying mechanisms are unclear. Current pharmacological methods cannot distinguish
between mGluR2 and mGluR3, and do not provide spatial, temporal, or cell type-specific targeting
in order to elucidate the function of specific mGluR2 sub-populations in the brain. This proposal
aims to use new optogenetic techniques to address current gaps in the understanding of
the expression, signaling, and behavioral changes elicited by presynaptic mGluR2 within
the mPFC–BLA circuit in a stress-induced rodent model of mood disorders.

## Key facts

- **NIH application ID:** 10241285
- **Project number:** 5F31MH123130-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Vanessa Gutzeit
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $18,540
- **Award type:** 5
- **Project period:** 2020-07-01 → 2021-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10241285

## Citation

> US National Institutes of Health, RePORTER application 10241285, Optopharmacological studies of presynaptic metabotropic glutamate receptor 2 in corticolimbic circuits (5F31MH123130-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10241285. Licensed CC0.

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