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

Abstract

Long-Term Potentiation (LTP) and Long-Term Depression (LTD) of excitatory synaptic transmission are considered as cellular basis of learning and memory. These two forms of synaptic plasticity have been mainly attributed to global changes in the number of synaptic AMPA-type glutamate receptor (AM-PAR) through a regulation of the diffusion/trapping balance at the PSD, exocytosis and endocytosis. While the precise molecular mechanisms at the base of LTP have been intensively investigated, the ones involved in LTD remains elusive. Here we combined super-resolution imaging technique, electrophysiology and modeling to describe the various modifications of AMPAR nanoscale organization and their effect on synaptic transmission in response to two different LTD protocols, based on the activation of either NMDA receptors or P2X receptors. While both type of LTD are associated with a decrease in synaptic AMPAR clustering, only NMDAR-dependent LTD is associated with a reorganization of PSD-95 at the nanoscale. This change increases the pool of diffusive AMPAR improving synaptic short-term facilitation through a post-synaptic mechanism. These results demonstrate that specific dynamic reorganization of synapses at the nanoscale during specific LTD paradigm allows to improve the responsiveness of depressed synapses. AMPA receptors | synaptic transmission | long-term depression | neuronal responsiveness | super-resolution imaging | electrophysiologyCorrespondence: eric.hosy@u-bordeaux.fr Compans et al. | bioRχiv | September 5, 2019 | 1-17

Engineering paralog-specific PSD-95 synthetic binders as potent and minimally invasive imaging probes

“…Morphological analysis of the objects and clusters provided dimensions consistent with previous reports for PSD-95-mEos2 fusions with PALM (Nair et al, 2013) or by STORM by labeling endogenous PSD-95 with antibodies (Compans et al, 2019) (length: 434.5 ± 39.9 and 178.0 ± 39.3 nm; width: 251.1 ± 39.2 and 99.1 ± 22.4 nm for the objects and clusters respectively, Fig. 5e).…”

Engineering paralog-specific PSD-95 recombinant binders as minimally interfering multimodal probes for advanced imaging techniques

“…This value is consistent with reported estimations of PSD-95 synaptic copies ( Chen et al, 2005 ; Sugiyama et al, 2005 ) and therefore suggests a close to stoichiometric labeling of the endogenous protein. Morphological analysis of the objects and clusters provided dimensions consistent with previous reports for PSD-95-mEos2 fusions with PALM ( Nair et al, 2013 ) or by STORM by labeling endogenous PSD-95 with antibodies ( Compans et al, 2019 ) (length: 434.5 ± 39.9 and 178.0 ± 39.3 nm; width: 251.1 ± 39.2 and 99.1 ± 22.4 nm for the objects and clusters, respectively, Figure 6e ). Together, these results indicate that Xph20-mEos3.2 provides an accurate snapshot of PSD-95 nanoscale distribution in fixed samples.…”