Distinct Nanoscale Calcium Channel and Synaptic Vesicle Topographies Contribute to the Diversity of Synaptic Function

Rebola, Nelson; Reva, Maria; Kirizs, Tekla; Szoboszlay, Miklos; Lőrincz, Andrea; Moneron, Gael; Nusser, Zoltán; DiGregorio, David A.

doi:10.1016/j.neuron.2019.08.014

Cited by 116 publications

(145 citation statements)

References 99 publications

(168 reference statements)

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“…This is contrary to what the isoform-specific CDF, as characterized in non-neuronal cells, would have predicted (Chaudhuri et al, 2004;Weyrer et al, 2019); it likely reflects instead a differential spatial relationship of the two isoforms to fuse-competent synaptic vesicles, with a tight and loose coupling configuration for Ca V 2.1[EFa] and Ca V 2.1[EFb], respectively (Figure 2Cc; Thalhammer et al, 2017). More in general, AS of Ca V 2.1 might underlie most of the intra-and inter-synaptic differences in nanoscale topographical arrangements of this channel, as recently revealed (Holderith et al, 2012;Nakamura et al, 2015;Rebola et al, 2019).…”

Section: Alternative Splicing Of P/q-type Ca 2+ Channels In Presynaptmentioning

confidence: 78%

Emerging Roles of Activity-Dependent Alternative Splicing in Homeostatic Plasticity

Thalhammer

Jaudon

Cingolani

2020

Front. Cell. Neurosci.

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Over the last two decades, a vast array of homeostatic plasticity adaptations, which enable neuronal networks to stabilize their activity in the face of external perturbations, have been identified. These involve adjustments in synaptic strength by means of preand postsynaptic mechanisms (homeostatic synaptic plasticity) and in intrinsic excitability (homeostatic intrinsic plasticity). Ultimately, both synaptic and intrinsic forms of homeostatic plasticity depend on changes in expression or activity of ion channels and synaptic proteins, which may occur at the gene, transcript, or protein level (Figure 1). By far, the most extensively investigated homeostatic mechanisms involve changes in protein function or localization by means of posttranslational modifications affecting protein-protein interactions and trafficking (reviewed in

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Section: Alternative Splicing Of P/q-type Ca 2+ Channels In Presynaptmentioning

confidence: 78%

Emerging Roles of Activity-Dependent Alternative Splicing in Homeostatic Plasticity

Thalhammer

Jaudon

Cingolani

2020

Front. Cell. Neurosci.

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“…We assessed whether Cav2.1 particles localize more closely to each other than expected by chance, and found that NNDs between real Cav2.1 particles are slightly, but significantly, smaller than those between simulated particles ( Figure 4 D). A few different models for the spatial relationship between Cav2.1 and release sites have been proposed [ 59 , 60 , 61 ]. In synapses displaying tight coupling between calcium influx and vesicle release sites a perimeter release model [ 59 , 60 ] and one-to-one correspondence of Cav2.1 clusters and vesicle release sites [ 61 ] have been proposed, while synapses with loose coupling were modeled by an exclusion zone model, with Cav2.1 being excluded from vesicle release sites but randomly distributed in the remaining synaptic area [ 59 ].…”

Section: Resultsmentioning

confidence: 99%

Deep Learning-Assisted High-Throughput Analysis of Freeze-Fracture Replica Images Applied to Glutamate Receptors and Calcium Channels at Hippocampal Synapses

Kleindienst

Montanaro

Bhandari

et al. 2020

IJMS

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The molecular anatomy of synapses defines their characteristics in transmission and plasticity. Precise measurements of the number and distribution of synaptic proteins are important for our understanding of synapse heterogeneity within and between brain regions. Freeze–fracture replica immunogold electron microscopy enables us to analyze them quantitatively on a two-dimensional membrane surface. Here, we introduce Darea software, which utilizes deep learning for analysis of replica images and demonstrate its usefulness for quick measurements of the pre- and postsynaptic areas, density and distribution of gold particles at synapses in a reproducible manner. We used Darea for comparing glutamate receptor and calcium channel distributions between hippocampal CA3-CA1 spine synapses on apical and basal dendrites, which differ in signaling pathways involved in synaptic plasticity. We found that apical synapses express a higher density of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and a stronger increase of AMPA receptors with synaptic size, while basal synapses show a larger increase in N-methyl-D-aspartate (NMDA) receptors with size. Interestingly, AMPA and NMDA receptors are segregated within postsynaptic sites and negatively correlated in density among both apical and basal synapses. In the presynaptic sites, Cav2.1 voltage-gated calcium channels show similar densities in apical and basal synapses with distributions consistent with an exclusion zone model of calcium channel-release site topography.

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“…RIM1α and RIM-BP2 form liquid condensates in vitro, and these condensates organize tethering of voltage-gated calcium channels 6,43 44 . In aggregate, it appears most likely that distinct liquid assemblies may exist within an active zone, one containing RIM1 and RIM-BP2 to tether calcium channels 3,6 , and a different phase with Liprin-α, RIM and Munc13-1.…”

Section: Interactions Of Presynaptic Liquid Phasesmentioning

confidence: 99%

Phosphorylation triggers presynaptic phase separation of Liprin-α3 to control active zone structure

Emperador-Melero

Wong

Wang

et al. 2020

Preprint

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Liquid-liquid phase separation enables the assembly of membrane-less subcellular compartments, but testing its biological functions has been difficult. The presynaptic active zone, protein machinery in nerve terminals that defines sites for neurotransmitter release, may be organized through phase separation. Here, we discover that the active zone protein Liprin-α3 rapidly and reversibly undergoes phase separation upon phosphorylation by PKC at a single site. RIM and Munc13 are co-recruited to membrane-attached condensates, and phospho-specific antibodies establish Liprin-α3 phosphorylation in vivo. At synapses of newly generated Liprin-α2/α3 double knockout mice, RIM, Munc13 and the pool of releasable vesicles were reduced. Re-expression of Liprin-α3 restored these defects, but mutating the Liprin-α3 phosphorylation site to abolish phase condensation prevented rescue. Finally, PKC activation acutely increased RIM, Munc13 and neurotransmitter release, which depended on the presence of phosphorylatable Liprin-α3. We conclude that Liprin-α3 phosphorylation rapidly triggers presynaptic phase separation to modulate active zone structure and function.

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Distinct Nanoscale Calcium Channel and Synaptic Vesicle Topographies Contribute to the Diversity of Synaptic Function

Cited by 116 publications

References 99 publications

Emerging Roles of Activity-Dependent Alternative Splicing in Homeostatic Plasticity

Emerging Roles of Activity-Dependent Alternative Splicing in Homeostatic Plasticity

Deep Learning-Assisted High-Throughput Analysis of Freeze-Fracture Replica Images Applied to Glutamate Receptors and Calcium Channels at Hippocampal Synapses

Phosphorylation triggers presynaptic phase separation of Liprin-α3 to control active zone structure

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