A trans-synaptic nanocolumn aligns neurotransmitter release to receptors

Abstract

Synaptic transmission is maintained by a delicate, subsynaptic molecular architecture, and even mild alterations in synapse structure drive functional changes during experience-dependent plasticity and pathological disorder1,2. Key to this architecture is how the distribution of presynaptic vesicle fusion sites corresponds to the position of receptors in the postsynaptic density. However, despite long recognition that this spatial relationship modulates synaptic strength3, it has not been precisely described, due in part to the limited resolution of light microscopy. Using localization microscopy, we report here that key proteins mediating vesicle priming and fusion are mutually co-enriched within nanometer-scaled subregions of the presynaptic active zone. Through development of a new method to map vesicle fusion positions within single synapses, we found that action potential evoked fusion was guided by this protein gradient and occurred preferentially in confined areas with higher local density of RIM within the active zones. These presynaptic RIM nanoclusters closely aligned with concentrated postsynaptic receptors and scaffolding proteins4–6, suggesting a transsynaptic molecular “nanocolumn.” Thus, we propose that the nanoarchitecture of the active zone directs action potential evoked vesicle fusion to occur preferentially at sites directly opposing postsynaptic receptor-scaffold ensembles. Remarkably, NMDA receptor activation triggered distinct phases of plasticity in which postsynaptic reorganization was followed by transsynaptic nanoscale realignment. This architecture thus suggests a simple organizational principle of CNS synapses to maintain and modulate synaptic efficiency.

Glutamatergic synapses are structurally and biochemically complex because of multiple plasticity processes: long-term potentiation, long-term depression, short-term potentiation and scaling

“…Moreover, the diameter of nanodomains has a relatively small variance (figure 3b), suggestive of a stereotyped modular subunit. Very recent work indicates that presynaptic release sites are located opposite to nanodomains [78], thus providing evidence for the kind of trans-synaptic module postulated in figure 2 [69]. Classical EM reconstructions of the synapse have also provided support for substructures on the presynaptic side.…”

Integrating Hebbian and homeostatic plasticity: introduction

“…By analysing data from structural studies at electron microscopy and super-resolution light microscopy levels, they model the relationship between synaptic gain and growth. Importantly, they draw on evidence that the pre-and postsynaptic elements of the synapse are aligned in nanocolumns [19] to argue that the two side of the synapse grow in register with one another during the late phase of LTP and that there are approximately 10 size states. Costa et al [20] also draw on a large body of literature that plasticity occurs at the pre-and postsynaptic loci, to explain the functional benefits of such a system.…”

Gradation (approx. 10 size states) of synaptic strength by quantal addition of structural modules

“…These two structures are exactly in register and covary in size over a large size range. Thus, growth of a synapse is a trans-synaptic process [7,12]. One limitation of EM is that the same structure cannot be studied both before and after LTP induction, and conclusions must, therefore, be based on statistical analysis.…”