Elsevier

Neurobiology of Disease

Volume 31, Issue 3, September 2008, Pages 406-412
Neurobiology of Disease

Impaired learning and memory in Pitx3 deficient aphakia mice: A genetic model for striatum-dependent cognitive symptoms in Parkinson's disease

https://doi.org/10.1016/j.nbd.2008.05.017Get rights and content

Abstract

Disorders of the basal ganglia such as Parkinson's disease (PD) and Huntington's disease are commonly thought of primarily as motor disorders; however, the cognitive symptoms of these diseases such as executive dysfunction, learning, memory and attention deficits are prominent and often more disabling than the hallmark motor symptoms. Cognitive features of PD are often neglected in preclinical studies of PD, likely due to the lack of available animal models to study them. Aphakia mice, which are deficient in the transcription factor Pitx3, model the selective nigrostriatal DA loss in PD. Here we report that aphakia mice are impaired in striatum-dependent cognitive tasks including rotarod learning, T-maze and inhibitory avoidance tasks, but not the striatum-independent social transmission of food preference task. These results suggest that some neuropsychiatric symptoms in PD are related to the pathophysiology of the disease rather than stress associated with disease burden, or medications used to treat PD. Furthermore aphakia mice may be used as a novel model of non-motor symptoms in PD.

Section snippets

Animals

Adult male ak mice used in this study were originally from The Jackson Laboratory (Bar Harbor, ME) (strain B6_C57BLKS-ak; JR942). They were outcrossed several times to C57BL/6 mice and maintained in the C57BL/6 background. Several breeding pairs were transferred, expanded, and maintained at the Animal Care Facility at McLean Hospital. Wild-type (wt) C57BL/6 mice were obtained from The Jackson Laboratory and used as control. Mice homozygous for retinal degeneration 1 (rd1 or Pde6brd1) mutation (

Results

The rotatord is used to measure balance, coordination, motor function and motor learning. Lesions of the striatum and cerebellum can impair rotarod performance and/or learning. As shown in Fig. 1 performance on the rotarod was similar across all three groups on day 1 which suggests lack of gross motor impairment in ak mice. Whereas wt and rd1 mice improved their performance over the next 2 days the learning curve for ak mice was nearly flat (Fig. 1, Top Panel). Analysis of the learning curves

Discussion

The major finding reported here is that deficiency of the transcription factor Pitx3 in mice results in striatum-dependent cognitive impairments. Importantly, the type of impairment we have observed in ak mice overlaps categorically with that observed in human PD since PD has been shown to involve both procedural (Allain et al., 1995, Thomas et al., 1996) and associative learning impairments (Vriezen and Moscovitch, 1990, Sprengelmeyer et al., 1995). These novel findings are interesting for

Acknowledgments

This work was supported by NIH grants MH48866 and DC006501, and an International Grant from Brain Research Center of the 21st Century Frontier Research Program funded by the Ministry of Science and Technology, the Republic of Korea. The authors are grateful to Jessie Kang for her excellent technical assistance.

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    Present address: Eli Lilly and Company, Lilly Research Laboratories, Lilly Corporate Center, Mail Drop 0510, Indianapolis, IN 46285, USA.

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