Cognitive Effects of Dopamine Depletion in the Context of Diminished Acetylcholine Signaling Capacity

A subset of patients with Parkinson’s disease acquires a debilitating dementia characterized by severe cognitive impairments (i.e. Parkinson’s Disease Dementia; PDD). PDD brains show extensive cholinergic loss as well as dopamine (DA)-depletion. We used a mutant mouse model to directly test whether combined cholinergicand DA depletion leads to a cognitive profile resembling PDD. Mice carrying heterozygous deletion of the high-affinity, hemicholinium-3 sensitive choline transporter (CHT) show reduced levels of acetylcholine throughout the brain. We achieved bilateral DA-depletion in CHT and wild-type (WT) littermates via intrastriatal infusion of 6-hydroxydopamine (6-OHDA) or vehicle. Executive function and memory were evaluated using rodent versions of cognitive tasks commonly used with human subjects: the set-shifting task and spatial and novel-object recognition paradigms. Our studies revealed impaired acquisition of attentional set in the set-shifting paradigm in WT-6OHDA and CHTvehicle that was exacerbated in the CHT-6OHDA mice. The object recognition test following a 24-hour delay was also impaired in CHT-6OHDA compared to all other groups. Treatment with acetylcholinesterase (AChE) inhibitors physostigmine (0.05 or 0.1 mg/kg) and donepezil (0.1 and 0.3 mg/kg) reversed the impaired object recognition of the CHT-6OHDA mice. Our data demonstrate an exacerbated cognitive phenotype with dual ACh-DA depletion as compared to either insult alone, with traits analogous to those observed in PDD patients. The results suggest that combined loss of DA and ACh may be sufficient for pathogenesis of specific cognitive deficits in PDD.