Imperial College London
Professor Dominic Withers

ProfessorDominicWithers

Faculty of Medicine, Institute of Clinical Sciences

Clinical Chair in Diabetes & Endocrinology
 
 
 
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Contact

 

d.withers

 
 
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Location

 

Hammersmith HospitalHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Ilse:2015:10.1186/s13024-015-0044-5,
author = {Ilse, S Pienaar and Sarah, E Gartside and Puneet, Sharma and De, Paola V and Sabine, Gretenkord and Dominic, Withers and Joanna, L Elson and David, T Dexter},
doi = {10.1186/s13024-015-0044-5},
journal = {Molecular Neurodegeneration},
title = {Pharmacogenetic stimulation of cholinergic pedunculopontine neurons reverses motor deficits in a rat model of Parkinson’s disease},
url = {http://dx.doi.org/10.1186/s13024-015-0044-5},
volume = {10},
year = {2015}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Background: Patients with advanced Parkinson's disease (PD) often present with axial symptoms, includingpostural- and gait difficulties that respond poorly to dopaminergic agents. Although deep brain stimulation (DBS) ofa highly heterogeneous brain structure, the pedunculopontine nucleus (PPN), improves such symptoms, theunderlying neuronal substrate responsible for the clinical benefits remains largely unknown, thus hamperingoptimization of DBS interventions. Choline acetyltransferase (ChAT)::Cre+ transgenic rats were sham-lesioned orrendered parkinsonian through intranigral, unihemispheric stereotaxic administration of the ubiquitin-proteasomalsystem 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 thehuman PPN. We have previously shown that the lactacystin rat model accurately reflects aspects of PD, including apartial 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 thelactacystin 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 recordingsrevealed increased spiking activity of PPTg putative cholinergic neurons during CNO-induced activation. c-Fosexpression in DREADD overexpressed ChAT-immunopositive (ChAT+) neurons of the PPTg was also increased byCNO administration, consistent with upregulated neuronal activation in this defined neuronal population.Conclusions: Overall, these findings provide evidence that functional modulation of PPN cholinergic neuronsalleviates parkinson
AU  - Ilse,S Pienaar
AU  - Sarah,E Gartside
AU  - Puneet,Sharma
AU  - De,Paola V
AU  - Sabine,Gretenkord
AU  - Dominic,Withers
AU  - Joanna,L Elson
AU  - David,T Dexter
DO  - 10.1186/s13024-015-0044-5
PY  - 2015///
SN  - 1750-1326
TI  - Pharmacogenetic stimulation of cholinergic pedunculopontine neurons reverses motor deficits in a rat model of Parkinson’s disease
T2  - Molecular Neurodegeneration
UR  - http://dx.doi.org/10.1186/s13024-015-0044-5
UR  - http://hdl.handle.net/10044/1/29895
VL  - 10
ER  -
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