title: Olfactory deficits in mice overexpressing human wildtype alpha-synuclein.
abstract: Accumulation of alpha-synuclein in neurons of the central and peripheral nervous system is a hallmark of sporadic Parkinson's disease (PD) and mutations that increase alpha-synuclein levels cause familial PD. Transgenic mice overexpressing alpha-synuclein under the Thy1 promoter (Thy1-aSyn) have high levels of alpha-synuclein expression throughout the brain but no loss of nigrostriatal dopamine neurons up to 8 months, suggesting that they may be useful to model pre-clinical stages of PD. Olfactory dysfunction often precedes the onset of the cardinal motor symptoms of PD by several years and includes deficits in odor detection, discrimination and identification. In the present study, we measured olfactory function in 3- and 9-month-old male Thy1-aSyn mice with a buried pellet test based on latency to find an exposed or hidden odorant, a block test based on exposure to self and non-self odors, and a habituation/dishabituation test based on exposure to non-social odors. In a separate group of mice, alpha-synuclein immunoreactivity was assessed in the olfactory bulb. Compared with wildtype littermates, Thy1-aSyn mice could still detect and habituate to odors but showed olfactory impairments in aspects of all three testing paradigms. Thy1-aSyn mice also displayed proteinase K-resistant alpha-synuclein inclusions throughout the olfactory bulb. These data indicate that overexpression of alpha-synuclein is sufficient to cause olfactory deficits in mice similar to that observed in patients with PD. Furthermore, the buried pellet and block tests provided sufficient power for the detection of a 50% drug effect, indicating their usefulness for testing novel neuroprotective therapies.
authors.affiliation: Department of Neurology and Neurobiology, The David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA. sfleming@ucla.edu
authors.forename: Sheila M
authors.initials: SM
authors.lastname: Fleming
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Tetreault
authors.forename: Caitlin K
authors.initials: CK
authors.lastname: Mulligan
authors.forename: Ché B
authors.initials: CB
authors.lastname: Hutson
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.forename: Marie-Françoise
authors.initials: MF
authors.lastname: Chesselet
mesh_terms: D000367:Age Factors; D000818:Animals; D001070:Appetitive Behavior; D001921:Brain / Q000378:metabolism; D003342:Corpus Striatum / Q000473:pathology; D004192:Discrimination, Psychological; D006185:Habituation, Psychophysiologic; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009830:Olfactory Bulb / Q000378:metabolism; D010300:Parkinson Disease / Q000150:complications / Q000378:metabolism; D012678:Sensation Disorders / Q000209:etiology* / Q000523:psychology; D012903:Smell; D013378:Substantia Nigra / Q000473:pathology; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein