LPHN3 is a postsynaptic adhesion G-protein-coupled receptor (GPCR) that mediates synapse formation in the hippocampus. It interacts with presynaptic teneurin and FLRT adhesion molecules, which are crucial for the establishment of Schaffer collateral synapses formed by CA3-region axons on CA1-region pyramidal neurons. Alternative splicing of LPHN3 controls its G-protein coupling specificity and its ability to recruit postsynaptic protein scaffolds. The Gαs-coupled LPHN3 splice variant selectively recruits postsynaptic scaffolds by enabling incorporation of LPHN3 onto the surface of phase-transitioned postsynaptic density protein complexes. LPHN3 has been implicated in attention deficit/hyperactivity disorder (ADHD) susceptibility. Variants of the LPHN3 gene have been associated with ADHD, and it is thought to modulate neuronal interaction, axon guidance, and synaptic plasticity, which are highly controlled and orchestrated during central nervous system development.
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