Nanoscale Structural Plasticity of the Active Zone Matrix Modulates Presynaptic Function

Abstract

SummaryThe active zone (AZ) matrix of presynaptic terminals coordinates the recruitment of voltage-gated calcium channels (VGCCs) and synaptic vesicles to orchestrate neurotransmitter release. However, the spatial organization of the AZ and how it controls vesicle fusion remain poorly understood. Here, we employ super-resolution microscopy and ratiometric imaging to visualize the AZ structure on the nanoscale, revealing segregation between the AZ matrix, VGCCs, and putative release sites. Long-term blockade of neuronal activity leads to reversible AZ matrix unclustering and presynaptic actin depolymerization, allowing for enrichment of AZ machinery. Conversely, patterned optogenetic stimulation of postsynaptic neurons retrogradely enhanced AZ clustering. In individual synapses, AZ clustering was inversely correlated with local VGCC recruitment and vesicle cycling. Acute actin depolymerization led to rapid (5 min) nanoscale AZ matrix unclustering. We propose a model whereby neuronal activity modulates presynaptic function in a homeostatic manner by altering the clustering state of the AZ matrix.

Rapid and Sustained Homeostatic Control of Presynaptic Exocytosis at a Central Synapse

“…Consistently, we uncovered elevated Ca 2+ -current density in the experimental conditions with increased pr, implying increased levels of presynaptic voltage-gated Ca 2+ channels. This observation is in line with previous light-microscopy based results from mammalian CNS synapses and the Drosophila NMJ (23,(66)(67)(68). 5…”

“…The expression of PHP depends on cell-culture age, with cultures older than two weeks compensating for prolonged activity deprivation through concomitant regulation of 20 presynaptic release, postsynaptic receptor abundance, and synapse number (19)(20)(21)(22). Despite evidence for compensatory changes in presynaptic structure and function (23)(24)(25)(26)(27), it is currently not well understood how these relate to the postsynaptic modifications during synaptic scaling. Moreover, it has remained largely elusive if PHP stabilizes the activity of native neural circuits (8,28,29).…”

Subsynaptic spatial organization as a regulator of synaptic strength and plasticity

“…AZ proteins can undergo vigorous reorganization on a time scale of minutes [45], which may consequently affect release site organization. For instance, following prolonged synaptic silencing, Bassoon was found to be less clustered while overall quantity remained unchanged [46]. This was associated with increased recruitment of presynaptic vesicle fusion machinery including Ca 2+ channels [46] and a decreased AZ-PSD distance [47], both presumably facilitating the known homeostatic increase of synaptic transmission.…”

“…For instance, following prolonged synaptic silencing, Bassoon was found to be less clustered while overall quantity remained unchanged [46]. This was associated with increased recruitment of presynaptic vesicle fusion machinery including Ca 2+ channels [46] and a decreased AZ-PSD distance [47], both presumably facilitating the known homeostatic increase of synaptic transmission. These activity-dependent reorganizations could dynamically modulate the properties of release sites, including not only P r but also spatial distribution (Fig.…”

Cannabis et neurodéveloppement

“…L'exposition au THC in utero ou en périnatal chez les rongeurs a été directement associée à de nombreux déficits cognitifs et émotionnels à long terme [15,16]. Les perturbations structurelles et fonctionnelles des systèmes dopaminergique et GABAergique observées [17][18][19] sont cohérentes avec celles observées chez l'homme, montrant que l'exposition au cannabis in utero entraîne une expression anormale des récepteurs dopaminergique D2 dans l'amygdale [4]. Des altérations de l'excitabilité des neurones et de la plasticité synaptique au niveau cortex préfrontal et de l'hippocampe ont aussi été rapportées [20].…”