# Modifying the Internal Globus Pallidus (GPi) in Parkinson's Disease: Role of Glutamate in Restoration

> **NIH VA I01** · PORTLAND VA MEDICAL CENTER · 2020 · —

## Abstract

Following the loss of nigrostriatal dopamine (DA), there is increased activity of glutamate neurons within the
subthalamic nucleus. These excitatory neurons project to the internal globus pallidus [GPi, or entopeduncular
nucleus (EPN) in the rodent], which utilizes the inhibitory neurotransmitter, GABA (gamma aminobutyric acid).
In Parkinson's disease (PD), deep brain stimulation (DBS) of the GPi results in improvement in motor function
and provides symptomatic relief. However in a rodent PD model, stimulation of the EPN/GPi did not result in
any protection against motor deficits or DA loss following acute intrastriatal infusion of 6-hydroxydopamine.
DBS could also be damaging the fibers of passage. However, directly decreasing GABA release from the
EPN/GPi neurons without affecting the fibers of passage could answer this concern. Since EPN/GPi neurons
utilize the vesicular GABA transporter (VGAT) for uptake of GABA into synaptic vesicles, deletion of this gene
would selectively decrease the release of GABA from those EPN/GPi neurons.
 Using the Cre/loxP recombinase gene technology where a specific gene can be silenced, effecting GABA
release from the EPN/GPi GABA neurons, can be achieved through deleting a targeted gene in the specific
brain area by injecting AAV-Cre into mice that are floxed for the GABA transporter, VGAT (Vgatflox/flox). To
determine if deletion of the Vgat gene in the GPi/EPN can be neuroprotective against DA terminal and cell
loss using the neurotoxin, MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), we find that unilateral
infusion of AAV-Cre-GFP (green fluorescent protein) into the EPN/GPi labeled approximately 80-90% of those
GABA neurons, as determined by GFP staining of EPN/GPi neurons, and increased GABA immuno-gold
labeling within the terminals of the motor thalamus (i.e., the EPN/GPi projects to the motor thalamus). As
measured by tyrosine hydroxylase (TH) immunoreactivity, this resulted in a bilateral protection from the loss
of DA terminals in the striatum and improved motor function. There was partial protection (~50%) from TH/DA
neuron loss in the substantia nigra pars compacta (SNpc). Following neurointervention, with unilateral AAV-
cre-GFP infusion into the EPN/GPi followed immediately by MPTP treatment (MPTP/Cre), we find that there is
improved motor strength and increased TH protein expression in the striatum and SNpc in the MPTP/Cre vs
MPTP only group. Using an additional PD animal model, in which AAV-alpha synuclein (A-Syn) is bilaterally
infused into the SNpc, prior deletion of the Vgat gene in the EPN/GPi with AAV-Cre (i.e., protection) resulted in
improved motor strength and blockade of TH/DA cell loss in the SNpc compared to the A-Syn only group.
 The overall goal of this project is to determine whether unilateral deletion of the Vgat gene, in 2
animal models of PD, within the EPN/GPi, following (i.e., neurorestoration, a more translationally
relevant model) either progressive administration of MPT...

## Key facts

- **NIH application ID:** 9898244
- **Project number:** 5I01BX001643-08
- **Recipient organization:** PORTLAND VA MEDICAL CENTER
- **Principal Investigator:** Charles Kenneth Meshul
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2010-10-01 → 2021-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898244

## Citation

> US National Institutes of Health, RePORTER application 9898244, Modifying the Internal Globus Pallidus (GPi) in Parkinson's Disease: Role of Glutamate in Restoration (5I01BX001643-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9898244. Licensed CC0.

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