Neural Glycosylphosphatidylinositol-Anchored Proteins in Synaptic Specification

Glycosylphosphatidylinositol (GPI)-anchored proteins are a specialized class of lipid-associated neuronal membrane proteins that perform diverse functions in the dynamic control of axon guidance, synaptic adhesion, cytoskeletal remodeling, and localized signal transduction, particularly at lipid raft domains. Recent studies have demonstrated that a subset of GPI-anchored proteins act as critical regulators of synapse development by modulating specific synaptic adhesion pathways via direct interactions with key synapse-organizing proteins. Additional studies have revealed that alteration of these regulatory mechanisms may underlie various brain disorders. In this review, we highlight the emerging role of GPI-anchored proteins as key synapse organizers that aid in shaping the properties of various types of synapses and circuits in mammals. Neural GPI-anchored proteins have important roles in various aspects of central nervous system development, including axon guidance, synapse formation, transmission, and plasticity. These proteins are enriched at lipid rafts via heterogeneous mechanisms, acting to orchestrate the activation of various synaptic membrane proteins and intracellular signaling components. GPI-anchored proteins interact with various co-receptors that coordinate distinct extracellular and intracellular mechanisms associated with synaptic adhesion pathways. Neural GPI-anchored proteins and their co-receptors are implicated in various brain disorders, and elucidation of the precise molecular mechanisms underlying their involvement is crucial in advancing our understanding of synapse and neural circuit development, and in developing targeted therapies for various brain disorders.