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. 2012;7(5):e36340.
doi: 10.1371/journal.pone.0036340. Epub 2012 May 11.

Haploinsufficiency of the E3 ubiquitin ligase C-terminus of heat shock cognate 70 interacting protein (CHIP) produces specific behavioral impairments

Bethann McLaughlin  1 , Matthew A Buendia, Tommy P Saborido, Amy M Palubinsky, Jeannette N Stankowski, Gregg D Stanwood
Affiliations

Haploinsufficiency of the E3 ubiquitin ligase C-terminus of heat shock cognate 70 interacting protein (CHIP) produces specific behavioral impairments

Bethann McLaughlin et al. PLoS One. 2012.

Abstract

The multifunctional E3 ubiquitin ligase CHIP is an essential interacting partner of HSP70, which together promote the proteasomal degradation of client proteins. Acute CHIP overexpression provides neuroprotection against neurotoxic mitochondrial stress, glucocorticoids, and accumulation of toxic amyloid fragments, as well as genetic mutations in other E3 ligases, which have been shown to result in familial Parkinson's disease. These studies have created a great deal of interest in understanding CHIP activity, expression and modulation. While CHIP knockout mice have the potential to provide essential insights into the molecular control of cell fate and survival, the animals have been difficult to characterize in vivo due to severe phenotypic and behavioral dysfunction, which have thus far been poorly characterized. Therefore, in the present study we conducted a battery of neurobehavioral and physiological assays of adult CHIP heterozygotic (HET) mutant mice to provide a better understanding of the functional consequence of CHIP deficiency. We found that CHIP HET mice had normal body and brain weight, body temperature, muscle tone and breathing patterns, but do have a significant elevation in baseline heart rate. Meanwhile basic behavioral screens of sensory, motor, emotional and cognitive functions were normative. We observed no alterations in performance in the elevated plus maze, light-dark preference and tail suspension assays, or two simple cognitive tasks: novel object recognition and spontaneous alternation in a Y maze. Significant deficits were found, however, when CHIP HET mice performed wire hang, inverted screen, wire maneuver, and open field tasks. Taken together, our data indicate a clear subset of behaviors that are altered at baseline in CHIP deficient animals, which will further guide whole animal studies of the effects of CHIP dysregulation on cardiac function, brain circuitry and function, and responsiveness to environmental and cellular stress.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Specific physiological alterations in CHIP HET mice.
Body weights (A) and brain weights (B) do not differ between CHIP WT and HET mice. (C) HET mice exhibit increased heart rate, but breath rate (D) and pO2 (E) are not significantly different from WT mice. *p<0.05.
Figure 2
Figure 2. Normal somatosensory function and grip strength in CHIP HET mice.
CHIP WT and HET mice exhibit normal paw withdrawal sensitivities to mechanical stimuli using von Frey filaments (A, B) and forepaw grip strength (C).
Figure 3
Figure 3. Motor abnormalities in CHIP HET mice.
CHIP HET mice exhibit a reduced latency to fall from a wire hang apparatus (A) and reduced time holding onto an inverted screen (B), but normal performance and learning on an accelerating rotarod (C). *p<0.05.
Figure 4
Figure 4. Open Field behaviors in CHIP WT and HET mice.
CHIP HET mice exhibit a significant decrease in motor stereotypies within an open field apparatus (B), but only a non-significant trend in total ambulatory distance (panel A, p = .135). However, upon separation of the open field into center and surround zones, there is a significant decrease in distance (C) and time spent in the center (D), suggesting an increase in anxiety-related behavior. *p<0.05, **p<0.01.
Figure 5
Figure 5. Anxiety-related behaviors in CHIP HET mice.
Neither the number of arm entries (A) nor time spent in arms (B) in an elevated plus maze demonstrates differences in anxiety responses. Similarly, there are no differences between CHIP WT and HET mice in a light-dark preference assay (C).
Figure 6
Figure 6. Cognitive and depressive behaviors in CHIP HET mice.
No differences between CHIP WT and HET mice were noted in Y maze spontaneous alternation (A), novel object recognition (B) or tail suspension test (C) assays.
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References

    1. Kiang JG, Tsokos GC. Heat shock protein 70 kDa: molecular biology, biochemistry, and physiology. Pharmacol Ther. 1998;80:183–201. - PubMed
    1. Dirnagl U, Becker K, Meisel A. Preconditioning and tolerance against cerebral ischaemia: from experimental strategies to clinical use. Lancet Neurol. 2009;8:398–412. - PMC - PubMed
    1. O'Duffy AE, Bordelon YM, McLaughlin B. Killer proteases and little strokes–how the things that do not kill you make you stronger. J Cereb Blood Flow Metab. 2007;27:655–668. - PMC - PubMed
    1. Lipton P. Ischemic cell death in brain neurons. Physiol Rev. 1999;79:1431–1568. - PubMed
    1. Arndt V, Rogon C, Höhfeld J. To be, or not to be — molecular chaperones in protein degradation. Cellular and Molecular Life Sciences. 2007;64:2525–2541. - PMC - PubMed

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