scholarly journals Caveolin-1 deficiency impairs synaptic transmission in hippocampal neurons

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Soulmee Koh ◽  
Wongyoung Lee ◽  
Sang Myun Park ◽  
Sung Hyun Kim
Keyword(s):  
Synaptic Transmission ◽  
Synaptic Vesicle ◽  
Hippocampal Neurons ◽  
Membrane Dynamics ◽  
Synaptic Membrane ◽  
Cellular Mechanisms ◽  
Caveolin 1 ◽  
Synaptic Vesicle Exocytosis ◽  
Vesicle Dynamics ◽  
Vesicle Exocytosis

AbstractIn addition to providing structural support, caveolin-1 (Cav1), a component of lipid rafts, including caveolae, in the plasma membrane, is involved in various cellular mechanisms, including signal transduction. Although pre-synaptic membrane dynamics and trafficking are essential cellular processes during synaptic vesicle exocytosis/synaptic transmission and synaptic vesicle endocytosis/synaptic retrieval, little is known about the involvement of Cav1 in synaptic vesicle dynamics. Here we demonstrate that synaptic vesicle exocytosis is significantly impaired in Cav1–knockdown (Cav1–KD) neurons. Specifically, the size of the synaptic recycled vesicle pool is modestly decreased in Cav1–KD synapses and the kinetics of synaptic vesicle endocytosis are somewhat slowed. Notably, neurons rescued by triple mutants of Cav1 lacking palmitoylation sites mutants show impairments in both synaptic transmission and retrieval. Collectively, our findings implicate Cav1 in activity-driven synaptic vesicle dynamics—both exocytosis and endocytosis—and demonstrate that palmitoylation of Cav1 is important for this activity.

scholarly journals Inositol pyrophosphates inhibit synaptotagmin-dependent exocytosis

2016 ◽  
Vol 113 (29) ◽  
pp. 8314-8319 ◽  
Author(s):  
Tae-Sun Lee ◽  
Joo-Young Lee ◽  
Jae Won Kyung ◽  
Yoosoo Yang ◽  
Seung Ju Park ◽  
...  
Keyword(s):  
Synaptic Vesicle ◽  
Neurotransmitter Release ◽  
Hippocampal Neurons ◽  
Vesicle Fusion ◽  
Synaptic Membrane ◽  
Synaptic Vesicle Exocytosis ◽  
Dependent Inhibition ◽  
Vesicle Exocytosis ◽  
Inositol Pyrophosphates

Inositol pyrophosphates such as 5-diphosphoinositol pentakisphosphate (5-IP7) are highly energetic inositol metabolites containing phosphoanhydride bonds. Although inositol pyrophosphates are known to regulate various biological events, including growth, survival, and metabolism, the molecular sites of 5-IP7 action in vesicle trafficking have remained largely elusive. We report here that elevated 5-IP7 levels, caused by overexpression of inositol hexakisphosphate (IP6) kinase 1 (IP6K1), suppressed depolarization-induced neurotransmitter release from PC12 cells. Conversely, IP6K1 depletion decreased intracellular 5-IP7 concentrations, leading to increased neurotransmitter release. Consistently, knockdown of IP6K1 in cultured hippocampal neurons augmented action potential-driven synaptic vesicle exocytosis at synapses. Using a FRET-based in vitro vesicle fusion assay, we found that 5-IP7, but not 1-IP7, exhibited significantly higher inhibitory activity toward synaptic vesicle exocytosis than IP6. Synaptotagmin 1 (Syt1), a Ca2+ sensor essential for synaptic membrane fusion, was identified as a molecular target of 5-IP7. Notably, 5-IP7 showed a 45-fold higher binding affinity for Syt1 compared with IP6. In addition, 5-IP7–dependent inhibition of synaptic vesicle fusion was abolished by increasing Ca2+ levels. Thus, 5-IP7 appears to act through Syt1 binding to interfere with the fusogenic activity of Ca2+. These findings reveal a role of 5-IP7 as a potent inhibitor of Syt1 in controlling the synaptic exocytotic pathway and expand our understanding of the signaling mechanisms of inositol pyrophosphates.

scholarly journals Insulin signaling controls neurotransmission via the 4eBP-dependent modification of the exocytotic machinery

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Rebekah Elizabeth Mahoney ◽  
Jorge Azpurua ◽  
Benjamin A Eaton
Keyword(s):  
Synaptic Vesicle ◽  
Insulin Signaling ◽  
Regulatory Mechanism ◽  
Neuronal Function ◽  
Cellular Mechanisms ◽  
Genetic Manipulations ◽  
Synaptic Vesicle Exocytosis ◽  
Vesicle Exocytosis ◽  
Dependent Modification ◽  
Synaptic Vesicle Fusion

Altered insulin signaling has been linked to widespread nervous system dysfunction including cognitive dysfunction, neuropathy and susceptibility to neurodegenerative disease. However, knowledge of the cellular mechanisms underlying the effects of insulin on neuronal function is incomplete. Here, we show that cell autonomous insulin signaling within the Drosophila CM9 motor neuron regulates the release of neurotransmitter via alteration of the synaptic vesicle fusion machinery. This effect of insulin utilizes the FOXO-dependent regulation of the thor gene, which encodes the Drosophila homologue of the eif-4e binding protein (4eBP). A critical target of this regulatory mechanism is Complexin, a synaptic protein known to regulate synaptic vesicle exocytosis. We find that the amounts of Complexin protein observed at the synapse is regulated by insulin and genetic manipulations of Complexin levels support the model that increased synaptic Complexin reduces neurotransmission in response to insulin signaling.

scholarly journals Piccolo modulation of Synapsin1a dynamics regulates synaptic vesicle exocytosis

2008 ◽  
Vol 181 (5) ◽  
pp. 831-846 ◽  
Author(s):  
Sergio Leal-Ortiz ◽  
Clarissa L. Waites ◽  
Ryan Terry-Lorenzo ◽  
Pedro Zamorano ◽  
Eckart D. Gundelfinger ◽  
...  
Keyword(s):  
Synaptic Vesicle ◽  
Active Zone ◽  
Hippocampal Neurons ◽  
Synapse Formation ◽  
Zone Formation ◽  
Homologous Protein ◽  
Synaptic Vesicle Exocytosis ◽  
Vesicle Exocytosis ◽  
Presynaptic Plasma Membrane ◽  
And Function

Active zones are specialized regions of the presynaptic plasma membrane designed for the efficient and repetitive release of neurotransmitter via synaptic vesicle (SV) exocytosis. Piccolo is a high molecular weight component of the active zone that is hypothesized to participate both in active zone formation and the scaffolding of key molecules involved in SV recycling. In this study, we use interference RNAs to eliminate Piccolo expression from cultured hippocampal neurons to assess its involvement in synapse formation and function. Our data show that Piccolo is not required for glutamatergic synapse formation but does influence presynaptic function by negatively regulating SV exocytosis. Mechanistically, this regulation appears to be calmodulin kinase II–dependent and mediated through the modulation of Synapsin1a dynamics. This function is not shared by the highly homologous protein Bassoon, which indicates that Piccolo has a unique role in coupling the mobilization of SVs in the reserve pool to events within the active zone.

scholarly journals Isoflurane inhibits synaptic vesicle exocytosis through reduced Ca2+ influx, not Ca2+-exocytosis coupling

2015 ◽  
Vol 112 (38) ◽  
pp. 11959-11964 ◽  
Author(s):  
Joel P. Baumgart ◽  
Zhen-Yu Zhou ◽  
Masato Hara ◽  
Daniel C. Cook ◽  
Michael B. Hoppa ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Synaptic Vesicle ◽  
Hippocampal Neurons ◽  
Volatile Anesthetic ◽  
Selective Inhibition ◽  
Nerve Terminals ◽  
General Anesthetics ◽  
Single Action ◽  
Presynaptic Mechanisms ◽  
Vesicle Exocytosis

Identifying presynaptic mechanisms of general anesthetics is critical to understanding their effects on synaptic transmission. We show that the volatile anesthetic isoflurane inhibits synaptic vesicle (SV) exocytosis at nerve terminals in dissociated rat hippocampal neurons through inhibition of presynaptic Ca2+ influx without significantly altering the Ca2+ sensitivity of SV exocytosis. A clinically relevant concentration of isoflurane (0.7 mM) inhibited changes in [Ca2+]i driven by single action potentials (APs) by 25 ± 3%, which in turn led to 62 ± 3% inhibition of single AP-triggered exocytosis at 4 mM extracellular Ca2+ ([Ca2+]e). Lowering external Ca2+ to match the isoflurane-induced reduction in Ca2+ entry led to an equivalent reduction in exocytosis. These data thus indicate that anesthetic inhibition of neurotransmitter release from small SVs occurs primarily through reduced axon terminal Ca2+ entry without significant direct effects on Ca2+-exocytosis coupling or on the SV fusion machinery. Isoflurane inhibition of exocytosis and Ca2+ influx was greater in glutamatergic compared with GABAergic nerve terminals, consistent with selective inhibition of excitatory synaptic transmission. Such alteration in the balance of excitatory to inhibitory transmission could mediate reduced neuronal interactions and network-selective effects observed in the anesthetized central nervous system.

scholarly journals Liprin-α3 controls vesicle docking and exocytosis at the active zone of hippocampal synapses

2018 ◽  
Vol 115 (9) ◽  
pp. 2234-2239 ◽  
Author(s):  
Man Yan Wong ◽  
Changliang Liu ◽  
Shan Shan H. Wang ◽  
Aram C. F. Roquas ◽  
Stephen C. Fowler ◽  
...  
Keyword(s):  
Synaptic Vesicle ◽  
Active Zone ◽  
Hippocampal Neurons ◽  
Stimulated Emission ◽  
Loss Of Function ◽  
Zone Structure ◽  
Vesicle Docking ◽  
Synaptic Vesicle Exocytosis ◽  
Vesicle Exocytosis ◽  
And Function

The presynaptic active zone provides sites for vesicle docking and release at central nervous synapses and is essential for speed and accuracy of synaptic transmission. Liprin-α binds to several active zone proteins, and loss-of-function studies in invertebrates established important roles for Liprin-α in neurodevelopment and active zone assembly. However, Liprin-α localization and functions in vertebrates have remained unclear. We used stimulated emission depletion superresolution microscopy to systematically determine the localization of Liprin-α2 and Liprin-α3, the two predominant Liprin-α proteins in the vertebrate brain, relative to other active-zone proteins. Both proteins were widely distributed in hippocampal nerve terminals, and Liprin-α3, but not Liprin-α2, had a prominent component that colocalized with the active-zone proteins Bassoon, RIM, Munc13, RIM-BP, and ELKS. To assess Liprin-α3 functions, we generated Liprin-α3–KO mice by using CRISPR/Cas9 gene editing. We found reduced synaptic vesicle tethering and docking in hippocampal neurons of Liprin-α3–KO mice, and synaptic vesicle exocytosis was impaired. Liprin-α3 KO also led to mild alterations in active zone structure, accompanied by translocation of Liprin-α2 to active zones. These findings establish important roles for Liprin-α3 in active-zone assembly and function, and suggest that interplay between various Liprin-α proteins controls their active-zone localization.

scholarly journals Fluoxetine prevents stimulation-dependent fatigue of synaptic vesicle exocytosis in hippocampal neurons

2010 ◽  
Vol 114 (3) ◽  
pp. 697-705 ◽  
Author(s):  
Andreas Wolfram Henkel ◽  
Oliver Welzel ◽  
Teja Wolfgang Groemer ◽  
Philipp Tripal ◽  
Andrea Rotter ◽  
...  
Keyword(s):  
Synaptic Vesicle ◽  
Hippocampal Neurons ◽  
Synaptic Vesicle Exocytosis ◽  
Vesicle Exocytosis

scholarly journals A common human brain-derived neurotrophic factor polymorphism leads to sustained depression of excitatory synaptic transmission by isoflurane in hippocampus

2022 ◽  
Author(s):  
Riley A. Williams ◽  
Kenneth W. Johnson ◽  
Francis S. Lee ◽  
Hugh C. Hemmings ◽  
Jimcy Platholi
Keyword(s):  
Synaptic Plasticity ◽  
Synaptic Transmission ◽  
Synaptic Vesicle ◽  
Neurotrophic Factor ◽  
Brain Derived Neurotrophic Factor ◽  
Synaptic Function ◽  
Excitatory Synaptic Transmission ◽  
Neurological Dysfunction ◽  
Synaptic Vesicle Exocytosis ◽  
Vesicle Exocytosis

Multiple presynaptic and postsynaptic targets have been identified for the reversible neurophysiological effects of general anesthetics on synaptic transmission and neuronal excitability. However, the synaptic mechanisms involved in persistent depression of synaptic transmission resulting in more prolonged neurological dysfunction following anesthesia are less clear. Here, we show that brain-derived neurotrophic factor (BDNF), a growth factor implicated in synaptic plasticity and dysfunction, enhances glutamate synaptic vesicle exocytosis, and that attenuation of vesicular BDNF release by isoflurane contributes to transient depression of excitatory synaptic transmission in mice. This reduction in synaptic vesicle exocytosis was irreversible in neurons that release less endogenous BDNF due to a polymorphism (BDNF Val66Met) compared to wild-type mouse hippocampal neurons following isoflurane exposure. These effects were prevented by exogenous application of BDNF. Our findings identify a role for a common human BDNF single nucleotide polymorphism (Val66Met; rs6265) in persistent changes of synaptic function following isoflurane exposure. These persistent alterations in excitatory synaptic transmission have important implications for the role of genotype in anesthetic effects on synaptic plasticity and neurocognitive function.

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