# Neuronal Targets and Mechanisms of Manganese Neurotoxicity

> **NIH NIH R01** · UNIVERSITY OF TEXAS AT AUSTIN · 2024 · $611,855

## Abstract

ABSTRACT
 The essential metal manganese (Mn) accumulates in the basal ganglia at elevated levels and induces motor
disease. Mn-induced motor disease is historically associated with occupational Mn exposure in adults. However,
environmental exposure to elevated Mn has emerged as a more recent public health problem in infants, children
and adolescents. Environmental Mn exposure in early-life substantially impairs motor function. But, the biology
of Mn-induced motor disease in early-life is poorly understood, and there are no treatments for this condition.
 The fundamental question of how early-life, environmental Mn exposure impacts dopaminergic (DAergic) or
GABAergic neurons in the basal ganglia that control movement to induce motor deficits is unanswered. This
major knowledge gap exists because prior mechanistic work focused on the effects of Mn in adults. But, results
from adults cannot be directly applied to early-life periods because environmental exposures are vastly different
from occupational, early-life stages are more sensitive to Mn, and the impact of occupational Mn exposure on
basal ganglia neurons is itself controversial. Our goal is to establish the effects of early-life, environmental Mn
exposure on basal ganglia DAergic and GABAergic neurons that lead to motor disease.
 We will use innovative mouse models developed in the previous cycle that provide the feasibility, for the first
time, to alter Mn levels specifically in DAergic or GABAergic neurons and isolate the role of the targeted neurons
in Mn-induced motor disease. Our models are based on the neuron-specific knockout or knockin of the critical
Mn efflux transporter SLC30A10. Pan-neuronal Slc30a10 knockouts had increased basal ganglia Mn levels and
exhibited early-life motor deficits. Notably, Mn levels were elevated in targeted neurons of DAergic-specific or
GABAergic-specific Slc30a10 knockouts, but only the DAergic-specific knockouts phenocopied the pan-neuronal
strain and developed early-life motor deficits. These novel results lead to the hypothesis that Mn induces motor
disease in early-life by targeting DAergic neurons. We will test our hypothesis through three specific aims.
 In Aim 1, we will use neuron-specific Slc30a10 knockout mice and test whether increasing Mn levels in
DAergic, but not GABAergic, neurons enhances sensitivity to Mn-induced motor deficits. In Aim 2, we will use
neuron-specific Slc30a10 knockin mice and test whether reducing Mn levels in DAergic, but not GABAergic,
neurons protects against Mn neurotoxicity. We will use a combination of behavioral, microscopy, and
neurochemical assays to distinguish between dysfunction or degeneration of DAergic or GABAergic neurons as
the cause of early-life Mn-induced motor disease. In Aim 3, we will use a pharmacological approach and test
whether dopamine agonists rescue early-life Mn-induced motor deficits. In totality, our studies (1) will establish
a definitive neuronal mechanism of motor disease induced by en...

## Key facts

- **NIH application ID:** 10895492
- **Project number:** 5R01ES024812-07
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** Somshuvra Mukhopadhyay
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $611,855
- **Award type:** 5
- **Project period:** 2016-01-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10895492

## Citation

> US National Institutes of Health, RePORTER application 10895492, Neuronal Targets and Mechanisms of Manganese Neurotoxicity (5R01ES024812-07). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10895492. Licensed CC0.

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