Necdin shapes serotonergic development and SERT activity modulating breathing in a mouse model for Prader-Willi syndrome
2017
Prader-Willi syndrome results from the disruption of a cluster of neighboring genes, including one called Necdin. Symptoms begin in early infancy and worsen with age. Affected children tend to develop an insatiable appetite, which often leads to obesity. They also experience serious problems with their
breathing. Chest infections, high altitude and
intense physicalactivity can be dangerous for children with Prader-Willi syndrome. This is because a slight shortage of oxygen may trigger
breathing difficultiesthat could prove fatal. The
brain cellsthat produce a chemical messenger called
serotoninhelp to control
breathing. Several lines of evidence suggest that loss of Necdin may trigger
breathing difficultiesin Prader-Willi syndrome via effects on the
serotoninsystem. First,
serotoninneurons produce the Necdin protein. Second, laboratory mice that lack the gene for Necdin have abnormally shaped
serotoninneurons. Third, these mice show
breathing difficultieslike those of individuals with Prader-Willi syndrome. But while this implies a connection between
serotonin, Necdin and
breathing difficulties, it falls short of establishing a causal link. Matarazzo et al. now reveal an increase in the quantity and activity of a protein called the
serotonin transporterin mutant mice that lacked the gene for Necdin compared to normal mice.
Serotonin transporterproteins mop up the
serotoninthat neurons release when they signal to one another. Neurons in the mutant mice take up more
serotoninthan their counterparts in normal mice; this means they have less
serotoninavailable for signaling. This may make it harder for the mutant mice to regulate their
breathing. Drugs called selective
serotonin-reuptake inhibitors (or SSRIs for short) can block the
serotonin transporter. These drugs, which include Fluoxetine (also called Prozac), are antidepressants. Matarazzo et al. show that SSRIs temporarily restore normal
breathingin young mice that lack the gene for Necdin. However, these drugs have harmful long-term effects on
breathingin non-mutant mice. Further studies should test whether short-term use of SSRIs could offer immediate relief for
breathing difficultiesin infants and children with Prader-Willi syndrome.
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