Characterization of early markers of disease in the mouse model of mucopolysaccharidosis IIIB
Abstract Background Mucopolysaccharidosis (MPS) IIIB, also known as Sanfilippo Syndrome B, is a devastating childhood disease. Unfortunately, there are currently no available treatments for MPS IIIB patients. Yet, animal models of lysosomal storage diseases have been valuable tools in identifying pr...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2024-04-01
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| Series: | Journal of Neurodevelopmental Disorders |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s11689-024-09534-z |
| _version_ | 1797199592578613248 |
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| author | Katherine B. McCullough Amanda Titus Kate Reardon Sara Conyers Joseph D. Dougherty Xia Ge Joel R. Garbow Patricia Dickson Carla M. Yuede Susan E. Maloney |
| author_facet | Katherine B. McCullough Amanda Titus Kate Reardon Sara Conyers Joseph D. Dougherty Xia Ge Joel R. Garbow Patricia Dickson Carla M. Yuede Susan E. Maloney |
| author_sort | Katherine B. McCullough |
| collection | DOAJ |
| description | Abstract Background Mucopolysaccharidosis (MPS) IIIB, also known as Sanfilippo Syndrome B, is a devastating childhood disease. Unfortunately, there are currently no available treatments for MPS IIIB patients. Yet, animal models of lysosomal storage diseases have been valuable tools in identifying promising avenues of treatment. Enzyme replacement therapy, gene therapy, and bone marrow transplant have all shown efficacy in the MPS IIIB model systems. A ubiquitous finding across rodent models of lysosomal storage diseases is that the best treatment outcomes resulted from intervention prior to symptom onset. Therefore, the aim of the current study was to identify early markers of disease in the MPS IIIB mouse model as well as examine clinically-relevant behavioral domains not yet explored in this model. Methods Using the MPS IIIB mouse model, we explored early developmental trajectories of communication and gait, and later social behavior, fear-related startle and conditioning, and visual capabilities. In addition, we examined brain structure and function via magnetic resonance imaging and diffusion tensor imaging. Results We observed reduced maternal isolation-induced ultrasonic vocalizations in MPS IIIB mice relative to controls, as well as disruption in a number of the spectrotemporal features. MPS IIIB also exhibited disrupted thermoregulation during the first two postnatal weeks without any differences in body weight. The developmental trajectories of gait were largely normal. In early adulthood, we observed intact visual acuity and sociability yet a more submissive phenotype, increased aggressive behavior, and decreased social sniffing relative to controls. MPS IIIB mice showed greater inhibition of startle in response to a pretone with a decrease in overall startle response and reduced cued fear memory. MPS IIIB also weighed significantly more than controls throughout adulthood and showed larger whole brain volumes and normalized regional volumes with intact tissue integrity as measured with magnetic resonance and diffusion tensor imaging, respectively. Conclusions Together, these results indicate disease markers are present as early as the first two weeks postnatal in this model. Further, this model recapitulates social, sensory and fear-related clinical features. Our study using a mouse model of MPS IIIB provides essential baseline information that will be useful in future evaluations of potential treatments. |
| first_indexed | 2024-04-24T07:18:12Z |
| format | Article |
| id | doaj.art-1e7bbcd0e48b4fcbb80760bcf8ba1676 |
| institution | Directory Open Access Journal |
| issn | 1866-1955 |
| language | English |
| last_indexed | 2024-04-24T07:18:12Z |
| publishDate | 2024-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neurodevelopmental Disorders |
| spelling | doaj.art-1e7bbcd0e48b4fcbb80760bcf8ba16762024-04-21T11:08:50ZengBMCJournal of Neurodevelopmental Disorders1866-19552024-04-0116112510.1186/s11689-024-09534-zCharacterization of early markers of disease in the mouse model of mucopolysaccharidosis IIIBKatherine B. McCullough0Amanda Titus1Kate Reardon2Sara Conyers3Joseph D. Dougherty4Xia Ge5Joel R. Garbow6Patricia Dickson7Carla M. Yuede8Susan E. Maloney9Department of Psychiatry, Washington University School of MedicineDepartment of Psychiatry, Washington University School of MedicineDepartment of Psychiatry, Washington University School of MedicineDepartment of Psychiatry, Washington University School of MedicineDepartment of Psychiatry, Washington University School of MedicineDepartment of Radiology, Washington University School of MedicineIntellectual and Developmental Disabilities Research Center, Washington University School of MedicineIntellectual and Developmental Disabilities Research Center, Washington University School of MedicineDepartment of Psychiatry, Washington University School of MedicineDepartment of Psychiatry, Washington University School of MedicineAbstract Background Mucopolysaccharidosis (MPS) IIIB, also known as Sanfilippo Syndrome B, is a devastating childhood disease. Unfortunately, there are currently no available treatments for MPS IIIB patients. Yet, animal models of lysosomal storage diseases have been valuable tools in identifying promising avenues of treatment. Enzyme replacement therapy, gene therapy, and bone marrow transplant have all shown efficacy in the MPS IIIB model systems. A ubiquitous finding across rodent models of lysosomal storage diseases is that the best treatment outcomes resulted from intervention prior to symptom onset. Therefore, the aim of the current study was to identify early markers of disease in the MPS IIIB mouse model as well as examine clinically-relevant behavioral domains not yet explored in this model. Methods Using the MPS IIIB mouse model, we explored early developmental trajectories of communication and gait, and later social behavior, fear-related startle and conditioning, and visual capabilities. In addition, we examined brain structure and function via magnetic resonance imaging and diffusion tensor imaging. Results We observed reduced maternal isolation-induced ultrasonic vocalizations in MPS IIIB mice relative to controls, as well as disruption in a number of the spectrotemporal features. MPS IIIB also exhibited disrupted thermoregulation during the first two postnatal weeks without any differences in body weight. The developmental trajectories of gait were largely normal. In early adulthood, we observed intact visual acuity and sociability yet a more submissive phenotype, increased aggressive behavior, and decreased social sniffing relative to controls. MPS IIIB mice showed greater inhibition of startle in response to a pretone with a decrease in overall startle response and reduced cued fear memory. MPS IIIB also weighed significantly more than controls throughout adulthood and showed larger whole brain volumes and normalized regional volumes with intact tissue integrity as measured with magnetic resonance and diffusion tensor imaging, respectively. Conclusions Together, these results indicate disease markers are present as early as the first two weeks postnatal in this model. Further, this model recapitulates social, sensory and fear-related clinical features. Our study using a mouse model of MPS IIIB provides essential baseline information that will be useful in future evaluations of potential treatments.https://doi.org/10.1186/s11689-024-09534-zSanfilippo BMucopolysaccharidosis IIIBLysosomal storage disorderUltrasonic vocalizationGaitFear conditioning |
| spellingShingle | Katherine B. McCullough Amanda Titus Kate Reardon Sara Conyers Joseph D. Dougherty Xia Ge Joel R. Garbow Patricia Dickson Carla M. Yuede Susan E. Maloney Characterization of early markers of disease in the mouse model of mucopolysaccharidosis IIIB Journal of Neurodevelopmental Disorders Sanfilippo B Mucopolysaccharidosis IIIB Lysosomal storage disorder Ultrasonic vocalization Gait Fear conditioning |
| title | Characterization of early markers of disease in the mouse model of mucopolysaccharidosis IIIB |
| title_full | Characterization of early markers of disease in the mouse model of mucopolysaccharidosis IIIB |
| title_fullStr | Characterization of early markers of disease in the mouse model of mucopolysaccharidosis IIIB |
| title_full_unstemmed | Characterization of early markers of disease in the mouse model of mucopolysaccharidosis IIIB |
| title_short | Characterization of early markers of disease in the mouse model of mucopolysaccharidosis IIIB |
| title_sort | characterization of early markers of disease in the mouse model of mucopolysaccharidosis iiib |
| topic | Sanfilippo B Mucopolysaccharidosis IIIB Lysosomal storage disorder Ultrasonic vocalization Gait Fear conditioning |
| url | https://doi.org/10.1186/s11689-024-09534-z |
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