Pharmacogenetic stimulation of cholinergic pedunculopontine neurons reverses motor deficits in a rat model of Parkinson’s disease
Author(s)
Type
Journal Article
Abstract
Background: Patients with advanced Parkinson's disease (PD) often present with axial symptoms, including
postural- and gait difficulties that respond poorly to dopaminergic agents. Although deep brain stimulation (DBS) of
a highly heterogeneous brain structure, the pedunculopontine nucleus (PPN), improves such symptoms, the
underlying neuronal substrate responsible for the clinical benefits remains largely unknown, thus hampering
optimization of DBS interventions. Choline acetyltransferase (ChAT)::Cre+ transgenic rats were sham-lesioned or
rendered parkinsonian through intranigral, unihemispheric stereotaxic administration of the ubiquitin-proteasomal
system inhibitor, lactacystin, combined with designer receptors exclusively activated by designer drugs (DREADD),
to activate the cholinergic neurons of the nucleus tegmenti pedunculopontine (PPTg), the rat equivalent of the
human PPN. We have previously shown that the lactacystin rat model accurately reflects aspects of PD, including a
partial loss of PPTg cholinergic neurons, similar to what is seen in the post-mortem brains of advanced PD patients.
Results: In this manuscript, we show that transient activation of the remaining PPTg cholinergic neurons in the
lactacystin rat model of PD, via peripheral administration of the cognate DREADD ligand, clozapine-N-oxide (CNO),
dramatically improved motor symptoms, as was assessed by behavioral tests that measured postural instability, gait,
sensorimotor integration, forelimb akinesia and general motor activity. In vivo electrophysiological recordings
revealed increased spiking activity of PPTg putative cholinergic neurons during CNO-induced activation. c-Fos
expression in DREADD overexpressed ChAT-immunopositive (ChAT+) neurons of the PPTg was also increased by
CNO administration, consistent with upregulated neuronal activation in this defined neuronal population.
Conclusions: Overall, these findings provide evidence that functional modulation of PPN cholinergic neurons
alleviates parkinsonian motor symptoms.
postural- and gait difficulties that respond poorly to dopaminergic agents. Although deep brain stimulation (DBS) of
a highly heterogeneous brain structure, the pedunculopontine nucleus (PPN), improves such symptoms, the
underlying neuronal substrate responsible for the clinical benefits remains largely unknown, thus hampering
optimization of DBS interventions. Choline acetyltransferase (ChAT)::Cre+ transgenic rats were sham-lesioned or
rendered parkinsonian through intranigral, unihemispheric stereotaxic administration of the ubiquitin-proteasomal
system inhibitor, lactacystin, combined with designer receptors exclusively activated by designer drugs (DREADD),
to activate the cholinergic neurons of the nucleus tegmenti pedunculopontine (PPTg), the rat equivalent of the
human PPN. We have previously shown that the lactacystin rat model accurately reflects aspects of PD, including a
partial loss of PPTg cholinergic neurons, similar to what is seen in the post-mortem brains of advanced PD patients.
Results: In this manuscript, we show that transient activation of the remaining PPTg cholinergic neurons in the
lactacystin rat model of PD, via peripheral administration of the cognate DREADD ligand, clozapine-N-oxide (CNO),
dramatically improved motor symptoms, as was assessed by behavioral tests that measured postural instability, gait,
sensorimotor integration, forelimb akinesia and general motor activity. In vivo electrophysiological recordings
revealed increased spiking activity of PPTg putative cholinergic neurons during CNO-induced activation. c-Fos
expression in DREADD overexpressed ChAT-immunopositive (ChAT+) neurons of the PPTg was also increased by
CNO administration, consistent with upregulated neuronal activation in this defined neuronal population.
Conclusions: Overall, these findings provide evidence that functional modulation of PPN cholinergic neurons
alleviates parkinsonian motor symptoms.
Date Issued
2015-09-23
Date Acceptance
2015-09-08
Citation
Molecular Neurodegeneration, 2015, 10
ISSN
1750-1326
Publisher
BioMed Central
Journal / Book Title
Molecular Neurodegeneration
Volume
10
Copyright Statement
© 2015 Pienaar et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
License URL
Sponsor
Rosetrees Trust
Medical Research Council
Grant Number
JS16/M205
Subjects
Science & Technology
Life Sciences & Biomedicine
Neurosciences
Neurosciences & Neurology
Cholinergic
Deep brain stimulation
DREADD
Parkinson's disease
Pedunculopontine nucleus
DEEP-BRAIN-STIMULATION
PROGRESSIVE SUPRANUCLEAR PALSY
PROTEIN-COUPLED RECEPTORS
SUBTHALAMIC NUCLEUS
MESOPONTINE TEGMENTUM
SUBSTANTIA-NIGRA
MECHANISMS
AKINESIA
LESIONS
SYSTEM
Neurology & Neurosurgery
1103 Clinical Sciences
1109 Neurosciences
0604 Genetics
Publication Status
Published
Article Number
47