scholarly journals Endogenous tagging reveals differential regulation of Ca2+ channels at single AZs during presynaptic homeostatic potentiation and depression

2017 ◽  
Author(s):  
Scott J. Gratz ◽  
Pragya Goel ◽  
Joseph J. Bruckner ◽  
Roberto X. Hernandez ◽  
Karam Khateeb ◽  
...  
Keyword(s):  
Information Flow ◽  
Neurotransmitter Release ◽  
Synaptic Strength ◽  
Live Imaging ◽  
Differential Regulation ◽  
Synaptic Function ◽  
Homeostatic Plasticity ◽  
Multiple Forms ◽  
Active Zones ◽  
Ca2 Channels

AbstractNeurons communicate through Ca2+-dependent neurotransmitter release at presynaptic active zones (AZs). Neurotransmitter release properties play a key role in defining information flow in circuits and are tuned during multiple forms of plasticity. Despite their central role in determining neurotransmitter release properties, little is known about how Ca2+ channel levels are modulated to calibrate synaptic function. We used CRISPR to tag the Drosophila CaV2 Ca2+ channel Cacophony (Cac) and investigated the regulation of endogenous Ca2+ channels during homeostatic plasticity in males in which all endogenous Cac channels are tagged. We found that heterogeneously distributed Cac is highly predictive of neurotransmitter release probability at individual AZs and differentially regulated during opposing forms of presynaptic homeostatic plasticity. Specifically, Cac levels at AZ are increased during chronic and acute presynaptic homeostatic potentiation (PHP), and live imaging during acute expression of PHP reveals proportional Ca2+ channel accumulation across heterogeneous AZs. In contrast, endogenous Cac levels do not change during presynaptic homeostatic depression (PHD), implying that the reported reduction in Ca2+ influx during PHD is achieved through functional adaptions to pre-existing Ca2+ channels. Thus, distinct mechanisms bi-directionally modulate presynaptic Ca2+ levels to maintain stable synaptic strength in response to diverse challenges, with Ca2+ channel abundance providing a rapidly tunable substrate for potentiating neurotransmitter release over both acute and chronic timescales.

scholarly journals Cul4 ubiquitin ligase cofactor DCAF12 promotes neurotransmitter release and homeostatic plasticity

2019 ◽  
Vol 218 (3) ◽  
pp. 993-1010 ◽  
Author(s):  
Lilian A. Patrón ◽  
Kei Nagatomo ◽  
David Tyler Eves ◽  
Mays Imad ◽  
Kimberly Young ◽  
...  
Keyword(s):  
Glutamate Receptor ◽  
Motor Neurons ◽  
Ubiquitin Ligase ◽  
Neurotransmitter Release ◽  
Neuromuscular Junctions ◽  
Synaptic Function ◽  
Homeostatic Plasticity ◽  
Independent Functions ◽  
Synaptic Boutons

We genetically characterized the synaptic role of the Drosophila homologue of human DCAF12, a putative cofactor of Cullin4 (Cul4) ubiquitin ligase complexes. Deletion of Drosophila DCAF12 impairs larval locomotion and arrests development. At larval neuromuscular junctions (NMJs), DCAF12 is expressed presynaptically in synaptic boutons, axons, and nuclei of motor neurons. Postsynaptically, DCAF12 is expressed in muscle nuclei and facilitates Cul4-dependent ubiquitination. Genetic experiments identified several mechanistically independent functions of DCAF12 at larval NMJs. First, presynaptic DCAF12 promotes evoked neurotransmitter release. Second, postsynaptic DCAF12 negatively controls the synaptic levels of the glutamate receptor subunits GluRIIA, GluRIIC, and GluRIID. The down-regulation of synaptic GluRIIA subunits by nuclear DCAF12 requires Cul4. Third, presynaptic DCAF12 is required for the expression of synaptic homeostatic potentiation. We suggest that DCAF12 and Cul4 are critical for normal synaptic function and plasticity at larval NMJs.

scholarly journals Reconstructing essential active zone functions within a synapse

2021 ◽  
Author(s):  
Chao Tan ◽  
Shan Shan H Wang ◽  
Giovanni de Nola ◽  
Pascal S Kaeser
Keyword(s):  
Fusion Protein ◽  
Synaptic Vesicle ◽  
Active Zone ◽  
Neurotransmitter Release ◽  
Molecular Machines ◽  
Vesicle Docking ◽  
Active Zones ◽  
Ca2 Channels

Active zones are molecular machines that control neurotransmitter release through synaptic vesicle docking and priming, and through coupling of these vesicles to Ca2+ entry. The complexity of active zone machinery has made it challenging to determine which mechanisms drive these roles in release. Here, we induce RIM+ELKS knockout to eliminate active zone scaffolding networks, and then reconstruct each active zone function. Re-expression of RIM1-Zn fingers positioned Munc13 on undocked vesicles and rendered them release-competent. Reconstitution of release-triggering required docking of these vesicles to Ca2+ channels. Fusing RIM1-Zn to CaVbeta4-subunits sufficed to restore docking, priming and release-triggering without reinstating active zone scaffolds. Hence, exocytotic activities of the 80 kDa CaVbeta4-Zn fusion protein bypassed the need for megadalton-sized secretory machines. These data define key mechanisms of active zone function, establish that fusion competence and docking are mechanistically separable, and reveal that active zone scaffolding networks are not required for release.

scholarly journals Rapid active zone remodeling consolidates presynaptic potentiation

2018 ◽  
Author(s):  
Mathias A. Böhme ◽  
Anthony W. McCarthy ◽  
Andreas T. Grasskamp ◽  
Christine B. Beuschel ◽  
Pragya Goel ◽  
...  
Keyword(s):  
Neurotransmitter Release ◽  
Release Site ◽  
Scaffold Proteins ◽  
Homeostatic Plasticity ◽  
Discrete Subset ◽  
Molecular Sequence ◽  
Central Neurons ◽  
Presynaptic Plasticity ◽  
Active Zones ◽  
Plastic Changes

AbstractSynaptic transmission is mediated by neurotransmitter release at presynaptic active zones (AZs) followed by postsynaptic neurotransmitter detection. Plastic changes in transmission maintain functionality during perturbations and enable memory formation. Postsynaptic plasticity targets neurotransmitter receptors, but presynaptic plasticity mechanisms directly regulating the neurotransmitter release apparatus remain largely enigmatic. Here we describe that AZs consist of nano-modular release site units and identify a molecular sequence adding more modules within minutes of plasticity induction. This requires cognate transport machinery and a discrete subset of AZ scaffold proteins. Structural remodeling is not required for the immediate potentiation of neurotransmitter release, but rather necessary to sustain this potentiation over longer timescales. Finally, mutations in Unc13 that disrupt homeostatic plasticity at the neuromuscular junction also impair shot-term memory when central neurons are targeted, suggesting that both forms of plasticity operate via Unc13. Together, while immediate synaptic potentiation capitalizes on available material, it triggers the coincident incorporation of modular release sites to consolidate stable synapse function.

scholarly journals Rapid homeostatic modulation of transsynaptic nanocolumn rings

2021 ◽  
Author(s):  
Paola Muttathukunnel ◽  
Patrick Frei ◽  
Sarah Perry ◽  
Dion Dickman ◽  
Martin Mueller
Keyword(s):  
Glutamate Receptor ◽  
Neurotransmitter Release ◽  
Information Transfer ◽  
Stimulated Emission ◽  
Homeostatic Plasticity ◽  
Synaptic Efficacy ◽  
Molecular Architecture ◽  
Neural Information ◽  
Active Zones ◽  
Chemical Synapses

Robust neural information transfer relies on a delicate molecular nano-architecture of chemical synapses. Neurotransmitter release is controlled by a specific arrangement of proteins within presynaptic active zones. How the specific presynaptic molecular architecture relates to postsynaptic organization, and how synaptic nano-architecture is transsynaptically regulated to achieve stable synaptic transmission remains enigmatic. Using time-gated stimulated emission depletion (gSTED) microscopy at the Drosophila neuromuscular junction, we here find that presynaptic nano-rings formed by the active-zone scaffold Bruchpilot (Brp) precisely align with postsynaptic glutamate receptor (GluR) rings. Individual rings harbor ~5 transsynaptically-aligned Brp-GluR nanocolumns. Intriguingly, acute GluR impairment rapidly triggers the formation of new transsynaptic nanocolumns on the minute time scale during homeostatic plasticity. We reveal distinct phases of structural transsynaptic homeostatic plasticity, with postsynaptic reorganization preceding presynaptic modulation. Finally, the auxiliary GluR subunit Neto-B; promotes structural and functional homeostatic plasticity. Thus, transsynaptic nanocolumns arrange in stereotypic rings that are rapidly modulated during homeostatic plasticity to stabilize synaptic efficacy.

scholarly journals Presynaptic DLG regulates synaptic function through the localization of voltage-activated Ca2+ Channels

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
César Astorga ◽  
Ramón A. Jorquera ◽  
Mauricio Ramírez ◽  
Andrés Kohler ◽  
Estefanía López ◽  
...  
Keyword(s):  
Synaptic Function ◽  
Ca2 Channels

scholarly journals Neuronal and synaptic plasticity in the visual thalamus in mouse models of glaucoma

2020 ◽  
Author(s):  
Matthew J. Van Hook ◽  
Corrine Monaco ◽  
Jennie C. Smith
Keyword(s):  
Mouse Models ◽  
Ganglion Cells ◽  
Brain Regions ◽  
Synaptic Function ◽  
Homeostatic Plasticity ◽  
Dorsal Lateral Geniculate Nucleus ◽  
Intrinsic Excitability ◽  
Dependent Manner ◽  
Functional Changes ◽  
Genetic Mouse Model

AbstractHomeostatic plasticity plays important roles in regulating synaptic and intrinsic neuronal function to stabilize output following perturbations to circuit activity. In glaucoma, a neurodegenerative disease of the visual system commonly associated with elevated intraocular pressure (IOP), early disease is associated with altered synaptic inputs to retinal ganglion cells (RGCs), changes in RGC intrinsic excitability, and deficits in optic nerve transport and energy metabolism. These early functional changes can precede RGC degeneration and are likely to alter RGC outputs to their target structures in the brain and thereby trigger homeostatic changes in synaptic and neuronal properties in those brain regions. In this study, we sought to determine whether and how neuronal and synaptic function is altered in the dorsal lateral geniculate nucleus (dLGN), an important RGC projection target in the thalamus, and how functional changes relate to IOP. We accomplished this using patch-clamp recordings from thalamocortical (TC) relay neurons in the dLGN in two established mouse models of glaucoma – the DBA/2J (D2) genetic mouse model and an inducible glaucoma model with intracameral microbead injections to elevate IOP. We found that the intrinsic excitability of TC neurons was enhanced in D2 mice and these functional changes were mirrored in recordings of TC neurons from microbead-injected mice. Notably, many neuronal properties were correlated with IOP in older D2 mice, but not younger D2 mice or microbead-injected mice. The frequency of miniature excitatory synaptic currents (mEPSCs) was reduced in both ages of D2 mice, and vGlut2 staining of RGC synaptic terminals was reduced in an IOP-dependent manner in older D2 mice. Among D2 mice, functional changes observed in younger mice without elevated IOP were distinct from those observed in older mice with elevated IOP and RGC degeneration, suggesting that glaucoma-associated changes to neurons in the dLGN might represent a combination of stabilizing/homeostatic plasticity at earlier stages and pathological dysfunction at later stages.

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