title: Deletion of the vesicular acetylcholine transporter from pedunculopontine/laterodorsal tegmental neurons modifies gait.
abstract: Postural instability and gait disturbances, common disabilities in the elderly and frequently present in Parkinson's disease (PD), have been suggested to be related to dysfunctional cholinergic signaling in the brainstem. We investigated how long-term loss of cholinergic signaling from mesopontine nuclei influence motor behaviors. We selectively eliminated the vesicular acetylcholine transporter (VAChT) in pedunculopontine and laterodorsal tegmental nuclei cholinergic neurons to generate mice with selective mesopontine cholinergic deficiency (VAChTEn1-Cre-flox/flox). VAChTEn1-Cre-flox/floxmice did not show any gross health or neuromuscular abnormality on metabolic cages, wire-hang and grip-force tests. Young VAChTEn1-Cre-flox/floxmice (2-5 months-old) presented motor learning/coordination deficits on the rotarod; moved slower, and had smaller steps on the catwalk, but showed no difference in locomotor activity on the open field. Old VAChTEn1-Creflox/floxmice (13-16 months-old) showed more pronounced motor learning/balance deficits on the rotarod, and more pronounced balance deficits on the catwalk. Furthermore, old mutants moved faster than controls, but with similar step length. Additionally, old VAChT-deficient mice were hyperactive. These results suggest that dysfunction of cholinergic neurons from mesopontine nuclei, which is commonly seen in PD, has causal roles in motor functions. Prevention of mesopontine cholinergic failure may help to prevent/improve postural instability and falls in PD patients. Read the Editorial Highlight for this article on page 688.
authors.affiliation: Robarts Research Institute, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada.
authors.forename: Helena
authors.initials: H
authors.lastname: Janickova
authors.affiliation: Robarts Research Institute, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada.|Department of Anatomy and Cell Biology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada.
authors.forename: Kaie
authors.initials: K
authors.lastname: Rosborough
authors.affiliation: Robarts Research Institute, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada.|Department of Anatomy and Cell Biology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Al-Onaizi
authors.affiliation: Robarts Research Institute, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada.|Department of Anatomy and Cell Biology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada.
authors.forename: Ornela
authors.initials: O
authors.lastname: Kljakic
authors.affiliation: Robarts Research Institute, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada.|Department of Anatomy and Cell Biology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada.
authors.forename: Monica S
authors.initials: MS
authors.lastname: Guzman
authors.affiliation: Robarts Research Institute, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada.|Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Gros
authors.affiliation: Robarts Research Institute, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada.|Department of Anatomy and Cell Biology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada.|Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada.
authors.forename: Marco A M
authors.initials: MA
authors.lastname: Prado
authors.affiliation: Robarts Research Institute, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada.|Department of Anatomy and Cell Biology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada.|Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada.
authors.forename: Vania F
authors.initials: VF
authors.lastname: Prado
mesh_terms: D000818:Animals; D020233:Gait Disorders, Neurologic / Q000235:genetics* / Q000523:psychology; D017353:Gene Deletion; D018737:Hand Strength; D007859:Learning Disabilities / Q000235:genetics; D008124:Locomotion; D008297:Male; D051379:Mice; D019957:Motor Skills Disorders / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000502:physiology*; D010275:Parasympathetic Nervous System / Q000166:cytology / Q000502:physiology; D045042:Pedunculopontine Tegmental Nucleus / Q000166:cytology / Q000378:metabolism*; D004856:Postural Balance; D011597:Psychomotor Performance; D013681:Tegmentum Mesencephali / Q000166:cytology / Q000378:metabolism; D050494:Vesicular Acetylcholine Transport Proteins / Q000235:genetics* / Q000502:physiology
chemical_list: C493460:Slc18a3 protein, mouse; D050494:Vesicular Acetylcholine Transport Proteins
keywords: Parkinson's disease; acetylcholine; balance; gait; motor disease; pedunculopontine