Necdin, Serotonin, and Breathing Problems in Prader-Willi Syndrome

  NECDIN is a gene that is deleted or inactivated in those with Prader-Willi syndrome , as it is found on chromosome 15 in the 15q11-q13 region. The gene product, Necdin, can be knocked out in mice, and a model for PWS thus emerges that displays some of the same respiratory and abnormal sleep breathing patterns that are often seen in humans with PWS. Necdin acts to stop cell death during the normal process of cell death in cells. The authors hypothesize that Necdin deficiency in mice (and perhaps even in humans) may result from deficits in the maturation and proper functioning of networks in the brain and set out to examine the relationship between Necdin and the neurotransmitter serotonin (5-HT) to better describe how 5-HT may affect Necdin-modulated breathing problems (Necdin Plays a Role in the Serotonergic Modulation of the Mouse Respiratory Network: Implication for PWS , Zanella et al., The Jl of Neurosci, 2008).

The authors first surveyed previously collected data of recordings of sleep breathing patterns in 10 PWS infants and 10 non-obese control subjects of matched age. They assessed the number of sleep apneas observed in each subject, which is typically counted by measuring how many times an individual has a reduction in airflow for three or more breaths in a set period of time. For infants with Prader-Willi syndrome between the ages of 1 and 50 months, apneas were reported in approximately 70% of individuals.
    The bulk of the study involved mice with the NECDIN gene knocked out (Ndn-KO mice). Breathing analyses and apnea assessments in these mice revealed sleep apneas similar to those seen in humans with PWS, thus providing support for using the mouse as a model for human PWS; in particular, the authors hold that the Ndn-KO mouse is a suitable model for examining aspects of respiratory and abnormal sleep breathing patterns.

To examine the significance or 5-HT on this system, 5-HT was administered to Ndn-KO mice. This treatment stabilized the breathing rhythms that were initially abnormal, although the precise mechanisms for this stabilization were unexplored. It appears that the neurons of the medulla (a region at the base of the brain that is critical for respiration) have altered 5-HT metabolism, and that Necdin is indeed expressed in the medulla, but not in regions that are typically associated with the primary control of respiratory rhythms. However, Necdin was found to be expressed by 5-HT neurons that are connected to the respiratory network, if not the primary medullary nuclei. A more detailed examination of 5-HT expression revealed that Necdin deficiency affects the shape and branching of 5-HT neural fibers, but does not affect the number of these fibers.

The main conclusion of this study is that Necdin, which we know is involved in the movement and normal growth of axons in the brain, can alter projections of 5-HT, which is intimately connected to the respiratory networks involved with apneas observed in Ndn-KO mice and, possibly, in humans with PWS. It is noted that PWS is a multi-gene syndrome, and NECDIN deficiency alone is never observed in humans. Rather, a complex interplay of genes and gene products produces the complex and varied syndrome. However, in a mouse model, any confirmation that the behaviors observed echo those seen in humans presents a promising opportunity to learn more about the mechanisms of individuals genes so that we can eventually put all of the pieces together and improve the quality of life for those with PWS who suffer from apneas and abnormal respiration.