scholarly journals Dynamin-related protein 1 is required for normal mitochondrial bioenergetic and synaptic function in CA1 hippocampal neurons

2015 ◽  
Vol 6 (4) ◽  
pp. e1725-e1725 ◽  
Author(s):  
L Y Shields ◽  
H Kim ◽  
L Zhu ◽  
D Haddad ◽  
A Berthet ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Synaptic Function ◽  
Related Protein

scholarly journals TNFα-induced AMPA-receptor trafficking in CNS neurons; relevance to excitotoxicity?

2004 ◽  
Vol 1 (3) ◽  
pp. 263-273 ◽  
Author(s):  
DMITRI LEONOUDAKIS ◽  
STEVEN P. BRAITHWAITE ◽  
MICHAEL S. BEATTIE ◽  
ERIC C. BEATTIE
Keyword(s):  
Cell Death ◽  
Inflammatory Response ◽  
Hippocampal Neurons ◽  
Neuronal Damage ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Cell Types ◽  
Synaptic Function ◽  
Ampar Trafficking ◽  
Novel Target

Injury and disease in the CNS increases the amount of tumor necrosis factor α (TNFα) that neurons are exposed to. This cytokine is central to the inflammatory response that occurs after injury and during prolonged CNS disease, and contributes to the process of neuronal cell death. Previous studies have addressed how long-term apoptotic-signaling pathways that are initiated by TNFα might influence these processes, but the effects of inflammation on neurons and synaptic function in the timescale of minutes after exposure are largely unexplored. Our published studies examining the effect of TNFα on trafficking of AMPA-type glutamate receptors (AMPARs) in hippocampal neurons demonstrate that glial-derived TNFα causes a rapid (<15 minute) increase in the number of neuronal, surface-localized, synaptic AMPARs leading to an increase in synaptic strength. This indicates that TNFα-signal transduction acts to facilitate increased surface localization of AMPARs from internal postsynaptic stores. Importantly, an excess of surface localized AMPARs might predispose the neuron to glutamate-mediated excitotoxicity and excessive intracellular calcium concentrations, leading to cell death. This suggests a new mechanism for excitotoxic TNFα-induced neuronal death that is initiated minutes after neurons are exposed to the products of the inflammatory response.Here we review the importance of AMPAR trafficking in normal neuronal function and how abnormalities that are mediated by glial-derived cytokines such as TNFα can be central in causing neuronal disorders. We have further investigated the effects of TNFα on different neuronal cell types and present new data from cortical and hippocampal neurons in culture. Finally, we have expanded our investigation of the temporal profile of the action of this cytokine relevant to neuronal damage. We conclude that TNFα-mediated effects on AMPAR trafficking are common in diverse neuronal cell types and very rapid in their onset. The abnormal AMPAR trafficking elicited by TNFα might present a novel target to aid the development of new neuroprotective drugs.

scholarly journals Nitric Oxide Transiently Converts Synaptic Inhibition to Excitation in Retinal Amacrine Cells

2006 ◽  
Vol 95 (5) ◽  
pp. 2866-2877 ◽  
Author(s):  
Brian Hoffpauir ◽  
Emily McMains ◽  
Evanna Gleason
Keyword(s):  
Nitric Oxide ◽  
Hippocampal Neurons ◽  
Reversal Potential ◽  
Amacrine Cells ◽  
Cell Types ◽  
Synaptic Function ◽  
Positive Shift ◽  
Gabaergic Synapses ◽  
Multiple Cell

Nitric oxide (NO) is generated by multiple cell types in the vertebrate retina, including amacrine cells. We investigate the role of NO in the modulation of synaptic function using a culture system containing identified retinal amacrine cells. We find that moderate concentrations of NO alter GABAA receptor function to produce an enhancement of the GABA-gated current. Higher concentrations of NO also enhance GABA-gated currents, but this enhancement is primarily due to a substantial positive shift in the reversal potential of the current. Several pieces of evidence, including a similar effect on glycine-gated currents, indicate that the positive shift is due to an increase in cytosolic Cl−. This change in the chloride distribution is especially significant because it can invert the sign of GABA- and glycine-gated voltage responses. Furthermore, current- and voltage-clamp recordings from synaptic pairs of GABAergic amacrine cells demonstrate that NO transiently converts signaling at GABAergic synapses from inhibition to excitation. Persistence of the NO-induced shift in ECl− in the absence of extracellular Cl− indicates that the increase in cytosolic Cl− is due to release of Cl− from an internal store. An NO-dependent release of Cl− from an internal store is also demonstrated for rat hippocampal neurons indicating that this mechanism is not restricted to the avian retina. Thus signaling in the CNS can be fundamentally altered by an NO-dependent mobilization of an internal Cl− store.

scholarly journals Light induced synaptic vesicle autophagy

2018 ◽  
Author(s):  
Sheila Hoffmann ◽  
Marta Orlando ◽  
Ewa Andrzejak ◽  
Thorsten Trimbuch ◽  
Christian Rosenmund ◽  
...  
Keyword(s):  
Synaptic Vesicle ◽  
Real Time ◽  
Hippocampal Neurons ◽  
Synaptic Function ◽  
Synaptic Proteins ◽  
Oxygen Species ◽  
Local Damage ◽  
Glutamatergic Synapses ◽  
Presynaptic Boutons ◽  
Presynaptic Proteins

AbstractThe regulated turnover of synaptic vesicle (SV) proteins is thought to involve the ubiquitin dependent tagging and degradation through endo-lysosomal and autophagy pathways. Yet, it remains unclear which of these pathways are used, when they become activated and whether SVs are cleared en-mass together with SV proteins or whether both are degraded selectively. Equally puzzling is how quickly these systems can be activated and whether they function in real time to support synaptic health. To address these questions, we have developed an imaging based system that simultaneously tags presynaptic proteins while monitoring autophagy. Moreover, by tagging SV proteins with a light activated reactive oxygen species (ROS) generator, Supernova, it was possible to temporally control the damage to specific SV proteins and assess their consequence to autophagy mediated clearance mechanisms and synaptic function. Our results show that, in mouse hippocampal neurons, presynaptic autophagy can be induced in as little as 5-10 minutes and eliminates primarily the damaged protein rather than the SV en-mass. Importantly, we also find that autophagy is essential for synaptic function, as light-induced damage to e.g. Synaptophysin only compromises synaptic function when autophagy is simultaneously blocked. These data support the concept that presynaptic boutons have a robust highly regulated clearance system to maintain not only synapse integrity, but also synaptic function.Significance StatementThe real-time surveillance and clearance of synaptic proteins is thought to be vital to the health, functionality and integrity of vertebrate synapses and is compromised in neurodegenerative disorders, yet the fundamental mechanisms regulating these systems remain enigmatic. Our analysis reveals that presynaptic autophagy is a critical part of a real-time clearance system at glutamatergic synapses capable of responding to local damage of synaptic vesicle proteins within minutes and to be critical for the ongoing functionality of these synapses. These data indicate that synapse autophagy is not only locally regulated but also crucial for the health and functionality of vertebrate presynaptic boutons.

scholarly journals Local translation in synaptic mitochondria influences synaptic transmission

2020 ◽  
Author(s):  
Roya Yousefi ◽  
Eugenio F. Fornasiero ◽  
Lukas Cyganek ◽  
Stefan Jakobs ◽  
Silvio O. Rizzoli ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hippocampal Neurons ◽  
Spatial Organization ◽  
Mitochondrial Gene ◽  
Cell Types ◽  
Synaptic Function ◽  
Synaptic Activity ◽  
Mitochondrial Gene Expression ◽  
Mitochondrial Translation ◽  
Ample Evidence

ABSTRACTMitochondria possess a small genome that codes for core subunits of the oxidative phosphorylation system, and whose expression is essential for energy production. Information on the regulation and spatial organization of mitochondrial gene expression in the cellular context has been difficult to obtain. Here we addressed this by devising an imaging approach to analyze mitochondrial translation, by following the incorporation of clickable non-canonical amino acids. We applied this method to multiple cell types, including hippocampal neurons, where we found ample evidence for mitochondrial translation in both dendrites and axons. Translation levels were surprisingly heterogeneous, were typically stronger in axons, and were independent of their distance from the cell soma, where mitochondria presumably descent from. Presynaptic mitochondrial translation correlated with local synaptic activity, and blocking mitochondria translation reduced synaptic function. Overall, these findings demonstrate that mitochondrial gene expression in neurons is intimately linked to neuronal function.

scholarly journals CD44: a novel synaptic cell adhesion molecule regulating structural and functional plasticity of dendritic spines

2016 ◽  
Vol 27 (25) ◽  
pp. 4055-4066 ◽  
Author(s):  
Matylda Roszkowska ◽  
Anna Skupien ◽  
Tomasz Wójtowicz ◽  
Anna Konopka ◽  
Adam Gorlewicz ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Dendritic Spines ◽  
Dendritic Spine ◽  
Rho Gtpases ◽  
Hippocampal Neurons ◽  
Synaptic Function ◽  
Adult Brain ◽  
Spine Shape ◽  
Neuronal Stimulation ◽  
And Function

Synaptic cell adhesion molecules regulate signal transduction, synaptic function, and plasticity. However, their role in neuronal interactions with the extracellular matrix (ECM) is not well understood. Here we report that the CD44, a transmembrane receptor for hyaluronan, modulates synaptic plasticity. High-resolution ultrastructural analysis showed that CD44 was localized at mature synapses in the adult brain. The reduced expression of CD44 affected the synaptic excitatory transmission of primary hippocampal neurons, simultaneously modifying dendritic spine shape. The frequency of miniature excitatory postsynaptic currents decreased, accompanied by dendritic spine elongation and thinning. These structural and functional alterations went along with a decrease in the number of presynaptic Bassoon puncta, together with a reduction of PSD-95 levels at dendritic spines, suggesting a reduced number of functional synapses. Lack of CD44 also abrogated spine head enlargement upon neuronal stimulation. Moreover, our results indicate that CD44 contributes to proper dendritic spine shape and function by modulating the activity of actin cytoskeleton regulators, that is, Rho GTPases (RhoA, Rac1, and Cdc42). Thus CD44 appears to be a novel molecular player regulating functional and structural plasticity of dendritic spines.

scholarly journals Berberine Alleviates Amyloid β-Induced Mitochondrial Dysfunction and Synaptic Loss

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Chunhui Zhao ◽  
Ping Su ◽  
Cui Lv ◽  
Limin Guo ◽  
Guoqiong Cao ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Amyloid Β ◽  
Isoquinoline Alkaloid ◽  
Synaptic Function ◽  
Protective Mechanism ◽  
Pathological Feature ◽  
Synaptic Loss ◽  
Beneficial Effects ◽  
Mitochondrial Motility ◽  
Cultured Hippocampal Neurons

Synaptic structural and functional damage is a typical pathological feature of Alzheimer’s disease (AD). Normal axonal mitochondrial function and transportation are vital to synaptic function and plasticity because they are necessary for maintaining cellular energy supply and regulating calcium and redox signalling as well as synaptic transmission and vesicle release. Amyloid-β (Aβ) accumulation is another pathological hallmark of AD that mediates synaptic loss and dysfunction by targeting mitochondria. Therefore, it is important to develop strategies to protect against synaptic mitochondrial damage induced by Aβ. The present study examined the beneficial effects of berberine, a natural isoquinoline alkaloid extracted from the traditional medicinal plant Coptis chinensis, on Aβ-induced mitochondrial and synaptic damage in primary cultured hippocampal neurons. We demonstrate that berberine alleviates axonal mitochondrial abnormalities by preserving the mitochondrial membrane potential and preventing decreases in ATP, increasing axonal mitochondrial density and length, and improving mitochondrial motility and trafficking in cultured hippocampal neurons. Although the underlying protective mechanism remains to be elucidated, the data suggest that the effects of berberine were in part related to its potent antioxidant activity. These findings highlight the neuroprotective and specifically mitoprotective effects of berberine treatment under conditions of Aβ enrichment.

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