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. 2012 Jan 19;1(1):1-14.
doi: 10.3390/jcm1010001.

Bone Marrow Transplantation Alters the Tremor Phenotype in the Murine Model of Globoid-Cell Leukodystrophy

Adarsh S Reddy  1 , David F Wozniak, Nuri B Farber, Joshua T Dearborn, Stephen C Fowler, Mark S Sands
Affiliations

Bone Marrow Transplantation Alters the Tremor Phenotype in the Murine Model of Globoid-Cell Leukodystrophy

Adarsh S Reddy et al. J Clin Med. .

Abstract

Tremor is a prominent phenotype of the twitcher mouse, an authentic genetic model of Globoid-Cell Leukodystrophy (GLD, Krabbe's disease). In the current study, the tremor was quantified using a force-plate actometer designed to accommodate low-weight mice. The actometer records the force oscillations caused by a mouse's movements, and the rhythmic structure of the force variations can be revealed. Results showed that twitcher mice had significantly increased power across a broad band of higher frequencies compared to wildtype mice. Bone marrow transplantation (BMT), the only available therapy for GLD, worsened the tremor in the twitcher mice and induced a measureable alteration of movement phenotype in the wildtype mice. These data highlight the damaging effects of conditioning radiation and BMT in the neonatal period. The behavioral methodology used herein provides a quantitative approach for assessing the efficacy of potential therapeutic interventions for Krabbe's disease.

Keywords: bone marrow transplantation; galactosylceramidase; globoid-cell leukodystrophy; lysosomal storage disease; tremor.

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Figures

Figure 1
Figure 1
Characterization of tremor in the Twi mice. Representative Fz time series recording from a Wt mouse (A) and a Twi mouse (B) over 12 seconds (each series is 6 s). The X-axis represents time and the Y-axis represents force the vertical force variation (Fz) recorded by the force plate actometer. A Fourier transformation performed on the Fz time series data yields a power spectrum that shows how much power (variance) the Fz variation contains at each frequency of oscillation. The power spectrum can then be further analyzed to yield peak power, frequency at peak power, center frequency, and bandwidth. These data are represented diagrammatically on a hypothetical power spectrum plot (C). The averaged power spectrum (D) of the Twi mice (solid black line) was shifted towards higher frequencies compared to the Wt mice (dashed gray line). The center frequency (E) was significantly increased in the Twi (open circles) compared to the Wt mice (filled squares). There was a significant increase in the band width (F) in the Twi compared to the Wt group. The peak power (G), frequency at peak power (H) and the power between 13 and 20 Hz (I) were significantly increased in the Twi group compared to the Wt group. The horizontal bars represent the mean and the error bars represent the SEM (***p < 0.001, **p < 0.01).
Figure 2
Figure 2
Characterization of locomotor activity in the twitcher mouse. The movement trajectory of representative Wt and Twi mice are shown in (A) and (B), respectively. Each panel represents the movement of the mouse for duration of 1 minute. The box in which each movement trajectory is plotted represents the inside wall of the 20 cm × 20 cm cage that confined the mouse to the load plate. Each point in the panel represents the XY location of the mouse at a certain point of time. The total distance traveled during 6 minutes is shown in (C). The total distance traveled by the Wt mice (filled squares) is significantly higher than that of the Twi mice (open circles). The horizontal bars represent the mean and the error bars represent the SEM (***p < 0.001).
Figure 3
Figure 3
Comparison of the tremor of the Twi mice with that of the tremor induced by harmaline. The average power spectrum (A) of the Twi mice (solid black line) reflected a broadband tremor and that of the WtH mice (solid gray line) showed a characteristic narrow band 12 Hz tremor. The response to harmaline was blunted in the TwiH mice (dashed black line). The center frequency (B) and bandwidth (C) were significantly increased in the Twi group (open circles) compared to the WtH group (filled diamonds), which exhibited the expected characteristic narrow band tremor typically induced by harmaline in mice. The peak power (D) was significantly increased in the WtH group compared to the Twi group. The frequency at peak power was significantly decreased in the WtH group compared to the Twi group. There was no significant difference in the center frequency, bandwidth, peak power and the frequency of peak power between the Twi and TwiH groups (plus symbols). Horizontal bars represent the mean and the error bars represent the SEM (***p < 0.001, **p < 0.01 and *p < 0.05).
Figure 4
Figure 4
Effect of BMT on power spectra. The averaged power spectrum (A) of the BmtWt group (dashed gray line) is shifted upward and rightward compared to the Wt group (solid gray line). Similarly, the averaged power spectrum in the BmtTwi group (dashed black line) is shifted upward across a broad frequency band compared to the Twi group (solid black line). The center frequency (B) was significantly increased in the BmtWt group (open triangles) compared to the Wt group (filled squares). There was no significant difference between the untreated mut (open circles) and BmtTwi groups (cross marks) in the center frequency. The peak power (C), frequency of peak power (D) and the power between 13 and 20 Hz (E) was significantly increased in the BmtWt group compared to the Wt group. Compared to the Twi group, the BmtTwi group showed no significant difference in the center frequency (B), peak power (C), frequency of peak power (D) and power between 13 and 20 Hz (E). The distance traveled by the BmtWt group was significantly decreased compared to the Wt group (F). The horizontal bars represent the mean and the error bars represent SEM (***p < 0.001, **p < 0.01 and *p < 0.05).
Figure 5
Figure 5
Harmaline tremor response in the BMT-treated animals. Averaged power spectra of various groups treated with harmaline (A). The averaged power spectrum of WtH group (solid gray line) appears different compared to the averaged power spectrum of the other groups in (A). The averaged power spectra of the BmtWtH (solid black line), TwiH (dashed black line), and BmtTwiH (solid gray line) appear very similar to each other. The center frequency (B) and the bandwidth (C) were significantly increased in the BmtWtH group (open triangles) compared to the WtH group (filled squares). The peak power (D) was significantly decreased in the BmtWtH group compared to the WtH group. There was no significant difference in center frequency, bandwidth or peak power between the TwiH (open circles) and BmtTwiH groups (cross marks). Horizontal bars represent the mean and the error bars represent the SEM (***p < 0.001, **p < 0.01 and *p < 0.05).
Figure 6
Figure 6
Histology- PAS and LFB staining. There are no identifiable PAS-positive cells in the cerebellum of the Wt animal (A). In the Twi (B), there are numerous pink multinucleated globoid cells (arrowheads). There is no obvious decrease in the number of PAS-positive cells in the BmtTwi group (C). Comparison of LFB staining in the cerebellar white matter (asterisk in D–F) and cerebellar folia shows a disruption of myelin architecture (blue staining) in the Twi (E) mouse compared to the Wt (D) animal. In the BmtTwi group (F), the myelin architecture remains disrupted, similar to the Twi group.
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