Sleep Fragmentation in TcMAC21 Mouse Model of Down Syndrome.

Background / Objective: Down syndrome (DS) is the most common chromosomal disorder worldwide, and approximately ¾ of individuals with DS demonstrate multifactorial sleep disturbances, including sleep apnea. As the effects of chromosome 21 triplication are complex, mouse models may provide valuable insights into the causal mechanisms of disordered sleep in DS. Although the recently developed transchromosomic TcMAC21 mouse model offers the closest genetic similarity to human DS, its sleep-wake architecture is unexplored. We hypothesized that TcMAC21 mice would exhibit sleep disruption similar to human DS, specifically with increased wakefulness and sleep fragmentation compared to the euploid controls. Methods: Using a non-invasive piezo-electric sleep recording system, we evaluated the sleep-wake architecture in male TcMAC21 (TS, n=9) and euploid (EU, n=9) male control mice under a 12-hour light/dark cycle. Analyzed metrics included: total sleep percentage, bout frequency, and bout length. Results: Compared to EU controls, TS mice exhibited a significant reduction in sleep bout duration (-29.0%, p = 0.02) during the dark phase, with primary effect during the first 8 hours, culminating in an overall decrease in total sleep percentage (-24.2%, p = 0.04). The light phase did not demonstrate statistically significant changes in total sleep percentage or sleep architecture. Conclusion: TcMAC21 mice demonstrated significant sleep fragmentation during the dark phase, potentially reproducing some aspects of sleep disruption in Down syndrome. Interestingly, these findings differed from descriptions of sleep in other DS animal models. Given the high degree of DS gene replication and non-mosaic nature of the TcMAC21 model, it may provide unique insight into the neurologic and anatomic mechanisms of sleep dysfunction in Down syndrome.