# Targeting cotransmission for circuit-specific pharmacotherapy

> **NIH NIH R01** · NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC · 2022 · $563,259

## Abstract

Dopamine neuron synapses — like most CNS synapses — release more than one neurotransmitter, with
roles that extend from development, to trophic support to more nuanced signaling. Dopamine neurons
release glutamate as a cotransmitter. Glutamate cotransmission confers striking heterogeneity to the
synaptic actions of dopamine neurons across their principal target neurons in the striatum. Tempering
dopamine neuron glutamate cotransmission by conditional reduction of the glutamate synthesizing enzyme
glutaminase, encoded by Gls1, reduces dopamine neuron glutamate cotransmission at phasic firing
frequencies. Mice with a global heterozygous reduction of Gls1 show potentiated latent inhibition, and are
less prone to psychostimulant sensitization, two behavioral effects involving aberrant salience attribution.
Strikingly, these two phenotypes are seen in mice with a Gls1 reduction restricted to their dopamine
neurons. The impact of the Gls1 reduction on dopamine neuron dependent behaviors runs counter to
symptoms of schizophrenia, arguing for therapeutic potential. The subtlety of the reduction, affecting
dopamine neuron glutamate cotransmission at phasic firing frequencies in the nucleus accumbens,
identifies key circuitry involved in salience attribution. The driving hypothesis of this proposal is that
dopamine neuron glutamate cotransmission is involved in salience attribution and that reducing
cotransmission has therapeutic potential for schizophrenia pharmacotherapy. In this project, we will
focus first on the synaptic impact of the Gls1 reduction on dopamine neuron dopamine and glutamate
release (Aim 1), recording in cholinergic interneurons that respond to both transmitters, and in striatal
projection neurons made into dopamine biosensors by expression of the dopamine-gated chloride channel
LGC-53, enabling comparison of the differential impact of the Gls1 reduction on DA and GLU signals. Then,
using an INTRSECT strategy (Aim 2), we will identify striatal dopamine neuron projections capable of
glutamate cotransmission, and use optogenetic stimulation to examine their role in salience attribution.
Finally, we will test glutaminase inhibition pharmacotherapy (Aim 3) showing first in brain slices that genetic
reduction of Gls1 and pharmacological inhibition of glutaminase similarly and preferentially impact
dopamine neuron glutamate cotransmission, and then induce a global Gls1 reduction in adulthood modeling
pharmacotherapy to show the behavioral impact. Finally, we will make a dopamine neuron-selective Gls1
reduction in adulthood to evaluate both the synaptic and behavioral impact. This research should increase
understanding of the role of dopamine neuron glutamate cotransmission and advance therapeutics based
on activity dependent modulation of glutamate release, specifically glutaminase inhibition as a novel
pharmacotherapy for schizophrenia.

## Key facts

- **NIH application ID:** 10410440
- **Project number:** 5R01MH117128-05
- **Recipient organization:** NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
- **Principal Investigator:** STEPHEN RAYPORT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $563,259
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10410440

## Citation

> US National Institutes of Health, RePORTER application 10410440, Targeting cotransmission for circuit-specific pharmacotherapy (5R01MH117128-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10410440. Licensed CC0.

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