In Prader-Willi syndrome (PWS), neuronal excitabilities and mutant neurons demonstrate substantially lower intensity than that of control neurons, according to a study published in Scientific Reports.
PWS is a genetic disorder that results in significant obsessive-compulsive and psychosis-related features in adult patients. These psychiatric manifestations have been linked to autism spectrum disorder (ASD).
“Given that PWS is caused by silencing of chromosome 15q11-13, synapse formation may be the key to understanding the mechanism of ASD phenotypes in PWS,” the authors of the report wrote.
Postsynaptic density protein (PSD-95) is thought to maintain the balance between brain excitation and inhibition. Although studies indicate that the maturation of spines containing PSD-95 correlates with ASD phenotypic manifestations, the underlying molecular mechanism remains a subject of debate. The authors identified Slit and Trk-like family member 1 as being involved in synaptogenesis. They concentrated their efforts on studying the synaptic formation and function of neurons differentiated in PWS patient-induced pluripotent stem (iPS) cells. In addition, they focused on NDN/MAGL2 single gene defect mutant iPS cells.
Read more about PWS etiology
The researchers obtained sets of human iPS cells from the RIKEN BioResource Center in Japan. They found that βIII tubulin expression in all the neurons was comparable to the level seen in the control. However, the researchers also noted that, in PWS, pre- and postsynaptic markers and mutant neurons were significantly lower compared with control neutrons. In addition, PSD-95 punctuation along βIII tubular neurites was reduced.
The researchers proceeded to measure neuronal excitability in PWS and mutant neurons. They discovered that, together with mutant neurons, these neutrons demonstrated significantly lower intensity than that of control neurons.
“Here, we show that the early stage of synapse and spine formation is affected by silencing genes on 15q11-13 and two of the silencing genes, NDN and MAGEL2 gene deletions, resulting in suppressed depolarization,” they concluded.
Reference
Soeda S, Ito D, Ogushi T, et al. Defects in early synaptic formation and neuronal function in Prader-Willi syndrome. Sci Rep. Published online July 25, 2023. doi:10.1038/s41598-023-39065-x
