title: Pharmacogenetic stimulation of cholinergic pedunculopontine neurons reverses motor deficits in a rat model of Parkinson's disease.
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.
authors.affiliation: Centre for Neuroinflammation and Neurodegeneration, Division of Brain Sciences, Faculty of Medicine, Imperial College London, London, W12 ONN, UK. i.pienaar@imperial.ac.uk.|Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, NE1 8ST, UK. i.pienaar@imperial.ac.uk.
authors.forename: Ilse S
authors.initials: IS
authors.lastname: Pienaar
authors.affiliation: Institute of Neuroscience, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Gartside
authors.affiliation: Centre for Neuroinflammation and Neurodegeneration, Division of Brain Sciences, Faculty of Medicine, Imperial College London, London, W12 ONN, UK.
authors.forename: Puneet
authors.initials: P
authors.lastname: Sharma
authors.affiliation: Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London, W12 0NN, UK.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: De Paola
authors.affiliation: Institute of Neuroscience, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Sabine
authors.initials: S
authors.lastname: Gretenkord
authors.affiliation: Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London, W12 0NN, UK.
authors.forename: Dominic
authors.initials: D
authors.lastname: Withers
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK.|Centre for Human Metabonomics, North-West University, Potchefstroom, South Africa.
authors.forename: Joanna L
authors.initials: JL
authors.lastname: Elson
authors.affiliation: Centre for Neuroinflammation and Neurodegeneration, Division of Brain Sciences, Faculty of Medicine, Imperial College London, London, W12 ONN, UK.
authors.forename: David T
authors.initials: DT
authors.lastname: Dexter
mesh_terms: D000818:Animals; D018678:Cholinergic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D059329:Cholinergic Neurons / Q000187:drug effects*; D046690:Deep Brain Stimulation / Q000379:methods; D004195:Disease Models, Animal; D010300:Parkinson Disease / Q000378:metabolism*; D045042:Pedunculopontine Tegmental Nucleus / Q000378:metabolism*; D010597:Pharmacogenetics / Q000379:methods; D020318:Rats, Long-Evans; D055647:Rats, Transgenic
chemical_list: D018678:Cholinergic Agents