Cognitive deficits in a mouse model of pre-manifest Parkinson's disease

• Published in: The European journal of neuroscience 2012-03, Vol.35 (6), p.870-882
• Main Authors: Magen, Iddo, Fleming, Sheila M., Zhu, Chunni, Garcia, Eddie C., Cardiff, Katherine M., Dinh, Diana, De La Rosa, Krystal, Sanchez, Maria, Torres, Eileen Ruth, Masliah, Eliezer, David Jentsch, J., Chesselet, Marie-Françoise
• Format: Article
• Language: English
• Subjects: Acetylcholine; alpha-Synuclein - genetics; alpha-Synuclein - metabolism; Animal models; Animals; Brain; Brain - metabolism; Brain - pathology; Cholinergic transmission; Cognition Disorders - etiology; Cognition Disorders - metabolism; Cognition Disorders - pathology; Cognitive ability; Data processing; Disease Models, Animal; Dopamine; Drugs; Humans; Immunohistochemistry; Male; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Movement disorders; Neostriatum; Nervous system; Neurodegenerative diseases; novel object recognition; novel place recognition; Operant conditioning; operant-reversal learning; Parkinson Disease - complications; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinson's disease; Pattern recognition; Promoters; Reversal learning; Spontaneous alternation; Synuclein; Y-maze; α-synuclein
• ISSN: 0953-816X; 1460-9568
• DOI: 10.1111/j.1460-9568.2012.08012.x

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. 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.