Necdin shapes serotonergic development and SERT activity modulating breathing in a mouse model for Prader-Willi syndrome

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 physical activity can be dangerous for children with Prader-Willi syndrome. This is because a slight shortage of oxygen may trigger breathing difficulties that could prove fatal. The brain cells that produce a chemical messenger called serotonin help to control breathing. Several lines of evidence suggest that loss of Necdin may trigger breathing difficulties in Prader-Willi syndrome via effects on the serotonin system. First, serotonin neurons produce the Necdin protein. Second, laboratory mice that lack the gene for Necdin have abnormally shaped serotonin neurons. Third, these mice show breathing difficulties like 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 transporter in mutant mice that lacked the gene for Necdin compared to normal mice. Serotonin transporter proteins mop up the serotonin that neurons release when they signal to one another. Neurons in the mutant mice take up more serotonin than their counterparts in normal mice; this means they have less serotonin available 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 breathing in young mice that lack the gene for Necdin. However, these drugs have harmful long-term effects on breathing in non-mutant mice. Further studies should test whether short-term use of SSRIs could offer immediate relief for breathing difficulties in infants and children with Prader-Willi syndrome.