Alternatively spliced mini-exon B in PTPδ regulates excitatory synapses through cell-type-specific trans-synaptic...

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Protein tyrosine phosphatase delta (PTPδ), encoded by PTPRD, is linked to neurological and neurodevelopmental disorders.
• PTPδ interacts with postsynaptic adhesion molecules via alternatively spliced mini-exons, meA and meB.
• The in vivo functions of PTPδ-meB remain largely uncharacterized.

Purpose of the Study:

• To investigate the in vivo function of the PTPδ-meB splice variant.
• To elucidate the role of PTPδ-meB in survival, synaptic function, and behavior.
• To identify molecular mechanisms underlying PTPδ-meB's effects on excitatory synapses.

Main Methods:

• Generation and analysis of homozygous PTPδ-meB-mutant mice (Ptprd-meB^-/-).
• Behavioral testing and electrophysiological recordings in heterozygous Ptprd-meB^+/- mice.
• Proteomic analysis of postsynaptic densities and investigation of IL1RAP-mutant mice.

Main Results:

• Homozygous Ptprd-meB^-/- mice exhibit reduced early postnatal survival.
• Heterozygous Ptprd-meB^+/- male mice display behavioral abnormalities and reduced excitatory synaptic transmission in dentate gyrus granule cells (DG-GCs).
• Decreased postsynaptic IL1RAP levels correlate with PTPδ-meB deficiency; IL1RAP-mutant mice show impaired excitatory transmission, while PTPδ-meB^+/- interneurons with low IL1RAP show enhanced excitatory transmission.

Conclusions:

• PTPδ-meB plays a critical role in early survival, synaptic plasticity, and behavior.
• PTPδ-meB regulates excitatory synapses in a cell-type-specific manner.
• The IL1RAP pathway is essential for PTPδ-meB's function in modulating synaptic transmission.