Neurexin-1γ drives synaptic transmission through structural integration of neurotransmitter release machinery and postsynaptic receptor nanodomains.
Synaptic transmission requires precise nanoscale alignment of presynaptic release machinery and postsynaptic receptor nanodomains. However, the molecular links bridging these subsynaptic elements remain unresolved. We identify mammalian neurexin-1γ as a presynaptic organizer that directly couples release sites to AMPAR nanodomains. Using complementary mouse lines, an epitope-tagged Nrxn1γ knockin and an Nrxn1γ knockout, and a multimodal approach, we find that neurexin-1γ is enriched at presynaptic release sites precisely opposite AMPAR nanoclusters. Nrxn1γ deletion perturbs synaptic nanoarchitecture, impairs vesicle docking and release, and disrupts transsynaptic nanocolumn alignment and AMPAR positioning, leading to broad deficits in both basal and evoked synaptic transmission, plasticity, and cognitive function. Mechanistically, neurexin-1γ directly binds AMPAR N-termini via its extracellular heparan sulfate glycans, anchoring them with nanoscale precision to neurotransmitter release sites. Our findings establish neurexin-1γ as a nanoscale transsynaptic bridge for optimal synaptic function and circuit activity, revealing an unconventional role for this minimal neurexin variant.