Pre-post synaptic alignment through neuroligin tunes synaptic transmission efficiency

The nanoscale organization of neurotransmitter receptors relative to pre-synaptic release sites is a fundamental determinant of both the amplitude and reliability of synaptic transmission. How modifications in the alignment between pre- and post-synaptic machineries affect synaptic current properties has only been addressed with computer modeling, and therefore remains hypothetical. Using dual-color single molecule based super-resolution microscopy, we found a strong spatial correlation between AMPA receptor (AMPAR) nanodomains and the post-synaptic adhesion protein neuroligin-1 (NLG1). Expression of a C-terminal truncated form of NLG1 disrupted this correlation without affecting the intrinsic organization of AMPAR nanodomains. Moreover, this NLG1 dominant-negative mutant significantly shifted the pre-synaptic release machinery from AMPAR synaptic clusters. Electrophysiology and computer modeling show that this physical shift is sufficient to induce a significant decrease in synaptic transmission. Thus, our results suggest the necessity for synapses to release glutamate in front of AMPAR nanodomains, to maintain a high efficiency of synaptic responses.