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Chronic nicotine improves cognitive and social impairment in mice overexpressing wild type α-synuclein

Subramaniam, Sudhakar R. and Magen, Iddo and Bove, Nicholas and Zhu, Chunni and Lemesre, Vincent and Dutta, Garima and Elias, Chris Jean and Lester, Henry A. and Chesselet, Marie-Francoise (2018) Chronic nicotine improves cognitive and social impairment in mice overexpressing wild type α-synuclein. Neurobiology of Disease, 117 . pp. 170-180. ISSN 0969-9961. http://resolver.caltech.edu/CaltechAUTHORS:20180611-095839803

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Abstract

In addition to dopaminergic and motor deficits, patients with Parkinson's disease (PD) suffer from non-motor symptoms, including early cognitive and social impairment, that do not respond well to dopaminergic therapy. Cholinergic deficits may contribute to these problems, but cholinesterase inhibitors have limited efficacy. Mice over-expressing α-synuclein, a protein critically associated with PD, show deficits in cognitive and social interaction tests, as well as a decrease in cortical acetylcholine. We have evaluated the effects of chronic administration of nicotine in mice over-expressing wild type human α-synuclein under the Thy1-promoter (Thy1-aSyn mice). Nicotine was administered subcutaneously by osmotic minipump for 6 months from 2 to 8 months of age at 0.4 mg/kg/h and 2.0 mg/kg/h. The higher dose was toxic in the Thy1-aSyn mice, but the low dose was well tolerated and both doses ameliorated cognitive impairment in Y-maze performance after 5 months of treatment. In a separate cohort of Thy1-aSyn mice, nicotine was administered at the lower dose for one month beginning at 5 months of age. This treatment partially eliminated the cognitive deficit in novel object recognition and social impairment. In contrast, chronic nicotine did not improve motor deficits after 2, 4 or 6 months of treatment, nor modified α-synuclein aggregation, tyrosine hydroxylase immunostaining, synaptic and dendritic markers, or microglial activation in Thy1-aSyn mice. These results suggest that cognitive and social impairment in synucleinopathies like PD may result from deficits in cholinergic neurotransmission and may benefit from chronic administration of nicotinic agonists.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1016/j.nbd.2018.05.018DOIArticle
ORCID:
AuthorORCID
Lester, Henry A.0000-0002-5470-5255
Additional Information:© 2018 Elsevier Inc. Received 19 March 2018, Revised 7 May 2018, Accepted 29 May 2018, Available online 1 June 2018. This work was supported by the Michael J. Fox Foundation (MJFF) Target Validation, 2011, by the Caltech-UCLA Joint Center for Translational Medicine (JCTM, UCLA-CALTECH-77857), by NIH grant AG-033954, by gifts to the Center for the Study of Parkinson's disease at UCLA, and by gifts from Louis and Janet Fletcher at Caltech. We thank Dr. Franziska Richter and Sheri McKinney for help in designing the study. We also thank undergraduate students Bansi Patel, Jacky Kwong, Sean Campeau and Diana Dinh for their help with behavior rating and histology. MFC has received honoraria (for service as a reviewer) and travel reimbursement from MJFF. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Funders:
Funding AgencyGrant Number
Michael J. Fox FoundationUNSPECIFIED
Caltech-UCLA Joint Center for Translational MedicineUNSPECIFIED
NIHAG-033954
Subject Keywords:Parkinson's disease; Mouse model; α-synuclein; Nicotine; Motor deficits; Cognitive deficits; Social impairment
Record Number:CaltechAUTHORS:20180611-095839803
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20180611-095839803
Official Citation:Sudhakar R. Subramaniam, Iddo Magen, Nicholas Bove, Chunni Zhu, Vincent Lemesre, Garima Dutta, Chris Jean Elias, Henry A. Lester, Marie-Francoise Chesselet, Chronic nicotine improves cognitive and social impairment in mice overexpressing wild type α-synuclein, Neurobiology of Disease, Volume 117, 2018, Pages 170-180, ISSN 0969-9961, https://doi.org/10.1016/j.nbd.2018.05.018. (http://www.sciencedirect.com/science/article/pii/S0969996118301566)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:86961
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:11 Jun 2018 20:49
Last Modified:26 Jun 2018 19:58

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