Synaptic Dysfunction in Human Neurons With Autism-Associated Deletions in PTCHD1-AS

Area of Science:

• Neuroscience
• Genetics
• Stem Cell Biology

Background:

• The Xp22.11 locus, including PTCHD1, DDX53, and PTCHD1-AS, is frequently disrupted in males with autism spectrum disorder (ASD).
• The functional impact of these genetic factors on ASD development remains unclear.

Purpose of the Study:

• To investigate the functional consequences of PTCHD1 locus deletions on neuronal function in ASD.
• To explore the role of PTCHD1 and PTCHD1-AS in the genetic risk of ASD and other neurodevelopmental disorders.

Main Methods:

• Generated induced pluripotent stem cells (iPSCs) from ASD subjects and controls with specific microdeletions.
• Assessed neuronal function using molecular techniques and electrophysiology.
• Utilized genome editing to study the impact of PTCHD1-AS exon deletion.

Main Results:

• ASD-derived neurons showed reduced miniature excitatory postsynaptic current frequency and N-methyl-D-aspartate receptor hypofunction.
• ASD-associated deletions frequently disrupted PTCHD1-AS exons.
• Deletion of PTCHD1-AS exon 3 altered splicing without affecting PTCHD1 expression and recapitulated synaptic deficits.

Conclusions:

• PTCHD1-AS deletions are significant risk factors for ASD.
• These deletions impact excitatory synaptic neurophysiology and contribute to synaptic impairment in ASD.
• The long noncoding RNA PTCHD1-AS plays a role in the etiology of ASD.