FLRT proteins are endogenous latrophilin ligands and regulate excitatory synapse development

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Latrophilins (LPHNs) are G protein-coupled receptors involved in synaptic exocytosis.
• Endogenous ligands and precise functions of LPHNs remain largely unknown.
• LPHN3 mutations are linked to attention deficit hyperactivity disorder (ADHD), suggesting roles in cognitive function.

Purpose of the Study:

• Identify endogenous ligands for latrophilins.
• Investigate the role of latrophilins and their ligands in glutamatergic synapse development.

Main Methods:

• Affinity chromatography and mass spectrometry to identify LPHN ligands.
• In vitro studies using cultured neurons to assess synapse density.
• In vivo studies using shRNA to reduce FLRT3 levels in animal models.

Main Results:

• The FLRT family of proteins identified as endogenous postsynaptic ligands for LPHNs.
• FLRT3 and LPHN3 ectodomains exhibit high-affinity interaction.
• Interference with FLRT3-LPHN3 interaction reduced excitatory synapse density in vitro.
• Reduced FLRT3 levels in vivo decreased afferent input strength and dendritic spine number.

Conclusions:

• FLRT3 is identified as an endogenous ligand for LPHN3.
• The LPHN3-FLRT3 interaction is critical for glutamatergic synapse development.
• This finding provides insights into the molecular mechanisms underlying cognitive function and disorders like ADHD.