SNX6-mediated subunit-specific secretory trafficking of AMPA receptors regulates synaptic function and plasticity.

The AMPA-type glutamate receptors (AMPARs) mediate the majority of fast excitatory synaptic transmission in the brain and are central to synaptic plasticity in excitatory neurons. Functional AMPARs are tetramers composed of different combinations of the channel-forming GluA1-GluA4 subunits, with GluA2 critically influencing receptor biophysics and trafficking. However, the mechanisms governing AMPAR subunit-specific trafficking and assembly in resting and activated neurons remain incompletely understood. Using hippocampal neurons and conditional knockout mice, we demonstrate that sorting nexin 6 (SNX6), a membrane trafficking regulator, selectively mediates sorting of newly synthesized GluA2 into the post-Golgi secretory pathway before its assembly with GluA1, a process essential for AMPAR delivery to the plasma membrane. Loss of SNX6 diverts GluA2 to lysosomal degradation, leading to decreases in constitutive and activity-dependent surface expression of AMPARs, impairment of AMPAR-mediated synaptic transmission and the NMDA-type glutamate receptor (NMDAR)-dependent long-term potentiation, and deficits in learning and memory. Collectively, our findings reveal a novel, subunit-specific mechanism for AMPAR biogenesis and trafficking, and underscore the importance of regulatory steps within the biosynthetic secretory pathway in synaptic receptor delivery.