Dynamic interplay between neurons and glia is critical to establish the proper structure and function of the nervous system. In particular, astrocytes are powerful regulators of the multiple steps of synapse development and function. However, we lack mechanistic understanding of how signaling molecules are delivered from astrocytes to neurons to regulate the synaptogenesis. In this proposal, we present evidence that GDE3, the major regulator of the glycosylphosphatidylinositol (GPI)-anchored proteins on the astrocyte surface, is required for synapse development and function. GDE3 facilitates the release of GPI-anchored proteins from astrocytes in two modes: GPI-shedding and extracellular vesicular release. In this proposal, we will define the release mechanism of the active form of synaptogenic factors and downstream effectors of GDE3. Importantly, we will determine the specific role of GPI-anchorage in synapse development and function in the developing brain. Our results will reveal a novel signaling mechanism of astrocyte-neuron communications and aid the design of alternative therapeutic interventions for diseases caused by synaptogenic defects.
Defects in synaptogenesis cause neurological diseases including autism, intellectual disability, and schizophrenia, for which therapeutic interventions are lacking. Astrocytes represent an attractive alternative target based on their role in providing neurons with synaptogenic molecules. By understanding how astrocyte surface enzymes regulate the release of the active form of synaptogenic factors, our research has the potential to identify new opportunities for neurological disease treatment.
