Pre-post synaptic alignment through neuroligin-1 tunes synaptic transmission efficiency

Abstract

The nanoscale organization of neurotransmitter receptors regarding pre-synaptic release sites is a fundamental determinant of the synaptic transmission amplitude and reliability. How modifications in the pre- and post-synaptic machinery alignments affects synaptic currents, has only been addressed with computer modelling. Using single molecule 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 truncated form of NLG1 disrupted this correlation without affecting the intrinsic AMPAR organization, shifting the pre-synaptic release machinery away from AMPAR nanodomains. Electrophysiology in dissociated and organotypic hippocampal rodent cultures shows these treatments significantly decrease AMPAR-mediated miniature and EPSC amplitudes. Computer modelling predicts that ~100 nm lateral shift between AMPAR nanoclusters and glutamate release sites induces a significant reduction in AMPAR-mediated currents. Thus, our results suggest the synapses necessity to release glutamate precisely in front of AMPAR nanodomains, to maintain a high synaptic responses efficiency.

Specific nanoscale synaptic reshuffling and control of short-term plasticity following NMDAR- and P2XR-dependent Long-Term Depression

“…Hence, we used dSTORM to measure PSD-95 nanoscale organization following both NMDAR-and P2XR-dependent LTD induction. As previously described, PSD-95 presents two levels of enrichment at synapses (11,12,31); the first one delineating the PSD, the second one corresponding to domains of local concentration into the PSD, beneath the AMPAR nanodomains and facing the glutamate release sites (9)(10)(11). Using tesselation-based clustering analysis (32), we extracted the 1st level (termed PSD-95 clusters), and the second level of clustering (termed PSD-95 nanoclusters) ( Figure 3A).…”

“…The average of the 5 responses (F) reveals no facilitation compared to control condition after ATP treatment(n=10 cells, mean +/-SEM, two-way ANOVA. For PPR variation, F(4,36)=7.73, p<0.0001, Dunnett's post-test found significant differences increase of PPR between PPR1/1 and PPR2/1, p=0.0163 at basal state, and between PPR1/1 and PPR2/1 or PPR3/1, p<0.0004 and p=0.0138 for P2XR-dependent LTD. For basal state vs P2XR-dependent LTD, F (1,9)…”

“…through this new prism. AMPAR-mediated current amplitude changes observed during LTD could arise from (i) a modification of the domain structure leading to a decrease in the packing of receptor (13); (ii) a misalignment between the preand the post-synaptic machinery (9,42) or more simply (iii) a depletion of the domains and overall decrease in synaptic AMPAR content. Here we report that both NMDA and ATP induce a synaptic depression based, at least partially, on postsynaptic nanoscale modifications.…”

“…The 3D-EM reconstruction contains all plasma membrane bounded components including dendrites, axons, astrocytic glia and the extracellular space itself, in a 6x6x5 um3 volume of hippocampal area CA1 stratum radiatum from adult rat. The AMPAR chemical kinetic properties were obtained from the well-established model published in Jonas et al, 1993, and the kinetic parameters were adjusted to fit with the recorded mEPSCs (see 9). Three surface properties are defined.…”

“…PSD-95) which anchor AMPAR complexes at the PSD, and the balanced activity of phosphatases and kinases regulating the affinity of the trapping (6)(7)(8). We and others have demonstrated that synaptic strength is not solely dependent on the quantity of glutamate per pre-synaptic vesicle and the number of post-synaptic AMPARs, but also rely on their nanoscale clusterization with respect to the pre-synaptic active zone (9)(10)(11)(12). Modeling sets that long term modifications in synaptic strength as observed with LTD or LTP can results from (i) a change in AMPAR density at synapse, (ii) a variation in receptor amount per cluster or (iii) a modification of the alignment between pre-synaptic release sites and AMPAR clusters (9,13).…”