Figure 10.

A proposed model for NDD development induced by pathogenic GRM7 mutations and rescued by AMN082. WT mGlu7 is stably expressed on the neuronal surface and necessary for axon outgrowth and presynaptic terminal development. Rapid degradation of mGlu7 variant proteins prevents axon outgrowth and presynaptic terminal development via the defective MAPK-cAMP-PKA signaling pathway and subsequent dysregulation of cytoskeletal dynamics. As some mGlu7 I154T is expressed on the neuronal surface, an mGlu7 agonist can restore impaired axon outgrowth and presynaptic terminal development (blue arrows). We propose that this scenario is the molecular basis for the development of mGlu7-related DDs/IDs and suggest mGlu7 as a potential therapeutic target for NDDs.