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Defects in early synaptic formation and neuronal function in Prader-Willi syndrome

Shuhei Soeda1, Daiki Ito2, Tomoe Ogushi2

  • 1Laboratory of Neurochemistry, College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Noji Higashi, Kusatsu, Shiga, 525-8577, Japan. soeda05@fc.ritsumei.ac.jp.

Scientific Reports
|July 25, 2023
PubMed

Insights

Prader-Willi syndrome (PWS) neurons show impaired synaptic formation and reduced neuronal excitability. These findings suggest potential neurodevelopmental defects in PWS, linked to downregulated SLITRK1.

Area of Science:

  • Neuroscience
  • Genetics
  • Developmental Biology

Background:

  • Prader-Willi syndrome (PWS) is an epigenetic disorder linked to chromosome 15q11-q13 gene deficiencies.
  • PWS is associated with neurodevelopmental and psychiatric conditions, including autism spectrum disorder.
  • Previous studies showed aberrant differentiation and transcriptomic dysregulation in PWS patient-derived induced pluripotent stem cells (iPSCs).

Purpose of the Study:

  • To investigate synaptic formation and function in neurons derived from PWS patient iPSCs.
  • To identify specific molecular defects contributing to neuronal dysfunction in PWS.

Main Methods:

  • RNA sequencing to identify downregulated genes in PWS neural stem cells (NSCs).
  • Differentiation of iPSCs from PWS patients and single gene defect mutants into neurons.
  • Analysis of pre- and postsynaptic markers (e.g., PSD-95) and neurite morphology.
  • Measurement of neuronal excitability via membrane potential responses to K+ stimulation.

Main Results:

  • SLITRK1 was identified as a downregulated gene in PWS NSCs.
  • Neurons derived from PWS and mutant iPSCs exhibited significantly lower levels of pre- and postsynaptic markers compared to controls.
  • PSD-95 puncta were decreased along neurites in PWS neurons.
  • Neuronal excitability was significantly reduced in PWS and mutant neurons.

Conclusions:

  • Downregulation of SLITRK1 and impaired synaptic development contribute to neuronal dysfunction in PWS.
  • These synaptic and functional deficits in PWS neurons may underlie neurodevelopmental phenotypes observed in the syndrome.
  • iPSC-derived neurons provide a valuable model for studying PWS neurobiology.

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