title: Cognitive deficits in a mouse model of pre-manifest Parkinson's disease.
abstract: Early cognitive deficits are increasingly recognized in patients with Parkinson's disease (PD), and represent an unmet need for the treatment of PD. These early deficits have been difficult to model in mice, and their mechanisms are poorly understood. α-Synuclein is linked to both familial and sporadic forms of PD, and is believed to accumulate in brains of patients with PD before cell loss. Mice expressing human wild-type α-synuclein under the Thy1 promoter (Thy1-aSyn mice) exhibit broad overexpression of α-synuclein throughout the brain and dynamic alterations in dopamine release several months before striatal dopamine loss. We now show that these mice exhibit deficits in cholinergic systems involved in cognition, and cognitive deficits in domains affected in early PD. Together with an increase in extracellular dopamine and a decrease in cortical acetylcholine at 4-6 months of age, Thy1-aSyn mice made fewer spontaneous alternations in the Y-maze and showed deficits in tests of novel object recognition (NOR), object-place recognition, and operant reversal learning, as compared with age-matched wild-type littermates. These data indicate that cognitive impairments that resemble early PD manifestations are reproduced by α-synuclein overexpression in a murine genetic model of PD. With high power to detect drug effects, these anomalies provide a novel platform for testing improved treatments for these pervasive cognitive deficits.
authors.affiliation: Department of Neurology, The David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA.
authors.forename: Iddo
authors.initials: I
authors.lastname: Magen
authors.forename: Sheila M
authors.initials: SM
authors.lastname: Fleming
authors.forename: Chunni
authors.initials: C
authors.lastname: Zhu
authors.forename: Eddie C
authors.initials: EC
authors.lastname: Garcia
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Cardiff
authors.forename: Diana
authors.initials: D
authors.lastname: Dinh
authors.forename: Krystal
authors.initials: K
authors.lastname: De La Rosa
authors.forename: Maria
authors.initials: M
authors.lastname: Sanchez
authors.forename: Eileen Ruth
authors.initials: ER
authors.lastname: Torres
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.forename: J David
authors.initials: JD
authors.lastname: Jentsch
authors.forename: Marie-Françoise
authors.initials: MF
authors.lastname: Chesselet
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D003072:Cognition Disorders / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D018782:Maze Learning; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D010300:Parkinson Disease / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein