# Microglia mediated suppression of dopamine induced neuronal responses and behavior

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $422,231

## Abstract

Project Summary
The proposal's objective is to identify the mechanisms that support microglia-mediated suppression of
dopamine responses. Microglia contribute to normal brain development by supporting neuronal survival
and brain tissue clearance from non-functional neurons and synapses. We identified a novel function of
microglia that involves the suppression of dopamine-induced behaviors in the adult brain. We found
that mice with a pan-brain or striatum-specific ablation of microglia display exaggerated dopamine-
induced motor activity and a propensity to seizures. These findings suggest a suppressive effect of
microglia on striatal neuron activation. Our preliminary data suggest that this effect could be elicited
directly by dopamine-induced microglia activation. We found that 10-15% of microglia in the striatum
but not in other brain regions express the dopamine D1 receptor. The expression of the dopamine D1
receptor by a subpopulation of striatal microglia suggests a potential novel negative feedback
mechanism where microglia tune neuronal response to dopamine after directly sensing/responding to
changes in the neurotransmitter level. Our proposal aims to elucidate the mechanism underlying
microglia-mediated suppression of dopamine responses and revolves around the following major
questions: Is there a specific subpopulation of striatal microglia that controls neuronal suppression, and
if yes, is it based on direct microglia triggering by dopamine? Does the suppressive activity of microglia
target a specific subpopulation of striatal neurons? What is the nature of the microglia-produced
mediators that impact neuronal responsiveness to dopamine? Our proposal relies heavily on in vivo
animal models, and we plan to generate new strains of transgenic mice that enable the manipulation of
microglia in the striatum. One of the innovative methodological aspects of the proposal involves state of
the art cell type-specific gene expression analysis in different neurons and microglia populations using
techniques developed by us that minimize aberrant changes in gene expression caused by cell
isolation procedures. In addition to elucidating the specific striatal microglia and neuron subpopulations
mediating the suppressive effect, our proposal aims to identify the microglia-produced regulators of
neuronal responses to dopamine. We found that the suppressive activity of microglia requires the
expression of the bromodomain-containing protein Brd4, which functions as a regulator of gene
transcription. Our data suggest that Brd4-bound microglia genes, especially those that are upregulated
by dopamine, may encode microglial suppressors of dopamine responses. Identification of these genes
is one of the major goals of the proposal, which we plan to achieve by using microglia-specific RNA and
chromatin analysis developed by us. Overall, our proposal has the potential to identify novel microglia-
based mechanisms that regulate neuronal responses to dopamine.

## Key facts

- **NIH application ID:** 10053343
- **Project number:** 5R01MH118329-03
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Anne Schaefer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $422,231
- **Award type:** 5
- **Project period:** 2019-01-01 → 2023-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10053343

## Citation

> US National Institutes of Health, RePORTER application 10053343, Microglia mediated suppression of dopamine induced neuronal responses and behavior (5R01MH118329-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10053343. Licensed CC0.

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