Feeding and swallowing deficits in a PWS mouse model and the treatment effects of oxytocin
Funding Summary
This project proposes a single overarching specific aim: Characterize feeding and swallowing deficits from birth to adulthood in the Madin KO mouse model of PWS and determine which deficits are mitigated by OT treatment delivered during the first week of life.
Lay Abstract
Individuals with Prader-Willi syndrome (PWS) experience feeding and swallowing difficulties beginning in infancy leading to malnutrition and loss of weight, and medical complications like aspiration pneumonia. However, the developmental progression of feeding and swallowing deficits remain poorly understood. The Del Ndn-Magel2 (Madin KO) mouse model of PWS exhibits deletion involving two PWS-associated genes, Ndn and Magel2, and show early-life phenotypes relevant to PWS. Previous studies have reported increased neonatal mortality, poor postnatal growth, and the absence of milk in the stomachs of deceased mutant neonates, suggesting possible feeding difficulties and/or respiratory dysfunction. Thus, the Madin KO mouse model provides an opportunity to investigate feeding and swallowing dysfunction in PWS.
This project proposed a single overarching Specific Aim which was to characterize feeding and swallowing deficits in the Del Ndn-Magel2 (Madin KO) mice model of PWS. We aimed to use our established feeding/swallowing phenotyping pipeline to study Madin KO mice and WT littermate controls at multiple post-weaning time points spanning 3-6 weeks of age.
This project proposed a single overarching Specific Aim which was to characterize feeding and swallowing deficits in the Del Ndn-Magel2 (Madin KO) mice model of PWS. We aimed to use our established feeding/swallowing phenotyping pipeline to study Madin KO mice and WT littermate controls at multiple post-weaning time points spanning 3-6 weeks of age.
Research Outcome
Persons with PWS experience feeding and swallowing deficits across the lifespan. During infancy, children with PWS may show swallowing difficulties and poor weight gain, which can result in dependence on feeding tubes for growth and survival. Understanding when feeding and swallowing problems begin, the underlying pathophysiology, and how these problems change with development is important for identifying better ways to assess and treat them. This project provides the first videofluoroscopic swallow study (VFSS)-based characterization of feeding and swallowing function in Del Ndn-Magel2 (Madin KO) mouse model of PWS after weaning. VFSS is a common method used to visualize the mouth, throat, and esophagus through video X-ray to assess swallowing problems. The Madin KO model reproduces several features associated with the human disorder, including impaired growth and significant early-life mortality. We initially hypothesized that Madin KO mice would display measurable feeding and swallowing abnormalities after weaning that mirror human PWS. Unexpectedly, our study showed that mice surviving to the post-weaning period had relatively preserved oral and pharyngeal swallowing function. Measures of feeding and swallowing matured with age, but we did not find significant differences between the Madin KO and wild-type (WT) mice. We also observed important findings that may help explain these results. Madin KO pups were underrepresented among the mice surviving to genotyping at 21 days old, and male Madin KO mice continued to have lower body weight after weaning, consistent with previous studies reporting embryonic and neonatal mortality and reduced post-natal growth in this model. Importantly, low body weight in male Madin KO mice was present despite the absence of detectable post-weaning oral and pharyngeal swallowing deficits. These findings suggest that feeding and swallowing difficulties may be more pronounced early in development, during the pre-weaning period, and that Madin KO mice surviving to weaning may represent a subset of animals with less severe early-life impairments or improvements in feeding and swallowing function by the post-weaning time points. Therefore, evaluating only post-weaning mice may not capture the full feeding and swallowing phenotype of this model.
This work underscores the need to investigate feeding and swallowing function during the pre-weaning period in Madin KO mice. This developmental stage is particularly relevant to PWS because human infants with PWS often experience their most significant feeding challenges early in life. Understanding what happens during this early developmental period may help us better understand the mechanisms underlying feeding and swallowing difficulties in PWS and provide a foundation for evaluating future treatments.
This work underscores the need to investigate feeding and swallowing function during the pre-weaning period in Madin KO mice. This developmental stage is particularly relevant to PWS because human infants with PWS often experience their most significant feeding challenges early in life. Understanding what happens during this early developmental period may help us better understand the mechanisms underlying feeding and swallowing difficulties in PWS and provide a foundation for evaluating future treatments.
Funded Year:
2024
Awarded to:
Teresa Lever, PhD
Amount:
$54,000
Institution:
University of Missouri-Columbia
Researcher:
