BDNF Enhances Quantal Neurotransmitter Release and Increases the Number of Docked Vesicles at the Active Zones of Hippocampal Excitatory Synapses

Presynaptic glutamate receptors (GluRs) modulate neurotransmitter release and are physiological targets for regulation during various forms of plasticity. Although much is known about the auxiliary subunits associated with postsynaptic GluRs, far less is understood about presynaptic auxiliary GluR subunits and their functions. At theDrosophilaneuromuscular junction, a presynaptic GluR,DKaiR1D, localizes near active zones and operates as an autoreceptor to tune baseline transmission and enhance presynaptic neurotransmitter release in response to diminished postsynaptic GluR functionality, a process referred to as presynaptic homeostatic potentiation (PHP). Here, we identify an auxiliary subunit that collaborates with DKaiR1D to promote these synaptic functions. This subunit, dSol-1, is the homolog of theCaenorhabditis elegansCUB (Complement C1r/C1s, Uegf, Bmp1) domain protein Sol-1. We find thatdSol-1functions in neurons to facilitate baseline neurotransmission and to enable PHP expression, properties shared withDKaiR1D. Intriguingly, presynaptic overexpression ofdSol-1is sufficient to enhance neurotransmitter release through aDKaiR1D-dependent mechanism. Furthermore,dSol-1is necessary to rapidly increase the abundance of DKaiR1D receptors near active zones during homeostatic signaling. Together with recent work showing the CUB domain protein Neto2 is necessary for the homeostatic modulation of postsynaptic GluRs in mammals, our data demonstrate that dSol-1 is required for the homeostatic regulation of presynaptic GluRs. Thus, we propose that CUB domain proteins are fundamental homeostatic modulators of GluRs on both sides of the synapse.

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Neurotransmitter Release: Priming at Presynaptic Active Zones

Encyclopedia of Neuroscience ◽

10.1007/978-3-540-29678-2_3954 ◽

2008 ◽

pp. 2834-2839

Author(s):

Hiroshi Kawabe ◽

Frederique Varoqueaux ◽

Nils Brose

Keyword(s):

Neurotransmitter Release ◽

Active Zones

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Postsynaptic Neuroligin-1 Mediates Presynaptic Endocytosis During Neuronal Activity

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2021.744845 ◽

2021 ◽

Vol 14 ◽

Author(s):

Jiaqi Keith Luo ◽

Holly Melland ◽

Jess Nithianantharajah ◽

Sarah L. Gordon

Keyword(s):

Ampa Receptors ◽

Neurotransmitter Release ◽

Synaptic Vesicles ◽

High Fidelity ◽

Excitatory Synapses ◽

Synaptic Efficacy ◽

Molecular Architecture ◽

Adhesion Protein ◽

Presynaptic Nerve Terminal ◽

Presynaptic Release

Fast, high-fidelity neurotransmission and synaptic efficacy requires tightly regulated coordination of pre- and postsynaptic compartments and alignment of presynaptic release sites with postsynaptic receptor nanodomains. Neuroligin-1 (Nlgn1) is a postsynaptic cell-adhesion protein exclusively localised to excitatory synapses that is crucial for coordinating the transsynaptic alignment of presynaptic release sites with postsynaptic AMPA receptors as well as postsynaptic transmission and plasticity. However, little is understood about whether the postsynaptic machinery can mediate the molecular architecture and activity of the presynaptic nerve terminal, and thus it remains unclear whether there are presynaptic contributions to Nlgn1-dependent control of signalling and plasticity. Here, we employed a presynaptic reporter of neurotransmitter release and synaptic vesicle dynamics, synaptophysin-pHluorin (sypHy), to directly assess the presynaptic impact of loss of Nlgn1. We show that lack of Nlgn1 had no effect on the size of the readily releasable or entire recycling pool of synaptic vesicles, nor did it impact exocytosis. However, we observed significant changes in the retrieval of synaptic vesicles by compensatory endocytosis, specifically during activity. Our data extends growing evidence that synaptic adhesion molecules critical for forming transsynaptic scaffolds are also important for regulating activity-induced endocytosis at the presynapse.

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Separation of presynaptic Cav2 and Cav1 channel function in synaptic vesicle exo- and endocytosis by the membrane anchored Ca2+ pump PMCA

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2106621118 ◽

2021 ◽

Vol 118 (28) ◽

pp. e2106621118

Author(s):

Niklas Krick ◽

Stefanie Ryglewski ◽

Aylin Pichler ◽

Arthur Bikbaev ◽

Torsten Götz ◽

...

Keyword(s):

Synaptic Vesicle ◽

Neurotransmitter Release ◽

Calcium Currents ◽

Short Term ◽

Triggered Release ◽

Presynaptic Terminals ◽

Dynamic Regulation ◽

Short Term Plasticity ◽

Separate Control ◽

Active Zones

Synaptic vesicle (SV) release, recycling, and plastic changes of release probability co-occur side by side within nerve terminals and rely on local Ca2+ signals with different temporal and spatial profiles. The mechanisms that guarantee separate regulation of these vital presynaptic functions during action potential (AP)–triggered presynaptic Ca2+ entry remain unclear. Combining Drosophila genetics with electrophysiology and imaging reveals the localization of two different voltage-gated calcium channels at the presynaptic terminals of glutamatergic neuromuscular synapses (the Drosophila Cav2 homolog, Dmca1A or cacophony, and the Cav1 homolog, Dmca1D) but with spatial and functional separation. Cav2 within active zones is required for AP-triggered neurotransmitter release. By contrast, Cav1 localizes predominantly around active zones and contributes substantially to AP-evoked Ca2+ influx but has a small impact on release. Instead, L-type calcium currents through Cav1 fine-tune short-term plasticity and facilitate SV recycling. Separate control of SV exo- and endocytosis by AP-triggered presynaptic Ca2+ influx through different channels demands efficient measures to protect the neurotransmitter release machinery against Cav1-mediated Ca2+ influx. We show that the plasma membrane Ca2+ ATPase (PMCA) resides in between active zones and isolates Cav2-triggered release from Cav1-mediated dynamic regulation of recycling and short-term plasticity, two processes which Cav2 may also contribute to. As L-type Cav1 channels also localize next to PQ-type Cav2 channels within axon terminals of some central mammalian synapses, we propose that Cav2, Cav1, and PMCA act as a conserved functional triad that enables separate control of SV release and recycling rates in presynaptic terminals.

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Macromolecular complexes at active zones: integrated nano-machineries for neurotransmitter release

Cellular and Molecular Life Sciences ◽

10.1007/s00018-014-1657-5 ◽

2014 ◽

Vol 71 (20) ◽

pp. 3903-3916 ◽

Cited By ~ 7

Author(s):

John Jia En Chua

Keyword(s):

Neurotransmitter Release ◽

Macromolecular Complexes ◽

Active Zones

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Reconstructing essential active zone functions within a synapse

10.1101/2021.11.21.469466 ◽

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.

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Neurotransmitter Release: Priming at Presynaptic Active Zones

10.1007/springerreference_117503 ◽

2012 ◽

Keyword(s):

Neurotransmitter Release ◽

Active Zones

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

10.1101/240051 ◽

2017 ◽

Cited By ~ 4

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.

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