Zurkovsky_2013_Dis.Model.Mech_6_171

Reference

Title : Cognitive effects of dopamine depletion in the context of diminished acetylcholine signaling capacity in mice - Zurkovsky_2013_Dis.Model.Mech_6_171
Author(s) : Zurkovsky L , Bychkov E , Tsakem EL , Siedlecki C , Blakely RD , Gurevich EV
Ref : Dis Model Mech , 6 :171 , 2013
Abstract :

A subset of patients with Parkinson's disease acquires a debilitating dementia characterized by severe cognitive impairments (i.e. Parkinson's disease dementia; PDD). Brains from PDD patients show extensive cholinergic loss as well as dopamine (DA) depletion. We used a mutant mouse model to directly test whether combined cholinergic and DA depletion leads to a cognitive profile resembling PDD. Mice carrying heterozygous deletion of the high-affinity, hemicholinium-3-sensitive choline transporter (CHT(HET)) show reduced levels of acetylcholine throughout the brain. We achieved bilateral DA depletion in CHT(HET) and wild-type (WT) littermates via intra-striatal infusion of 6-hydroxydopamine (6-OHDA), or used vehicle as control. 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 CHT(HET)-vehicle mice that was exacerbated in the CHT(HET)-6OHDA mice. The object recognition test following a 24-hour delay was also impaired in CHT(HET)-6OHDA mice compared with 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(HET)-6OHDA mice. Our data demonstrate an exacerbated cognitive phenotype with dual ACh and DA depletion as compared with either insult alone, with traits analogous to those observed in PDD patients. The results suggest that combined loss of DA and ACh could be sufficient for pathogenesis of specific cognitive deficits in PDD.

PubMedSearch : Zurkovsky_2013_Dis.Model.Mech_6_171
PubMedID: 22864020

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Citations formats

Zurkovsky L, Bychkov E, Tsakem EL, Siedlecki C, Blakely RD, Gurevich EV (2013)
Cognitive effects of dopamine depletion in the context of diminished acetylcholine signaling capacity in mice
Dis Model Mech 6 :171

Zurkovsky L, Bychkov E, Tsakem EL, Siedlecki C, Blakely RD, Gurevich EV (2013)
Dis Model Mech 6 :171